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Correction: Association between Technology Development and Rounder Substituted-lh-Indole-2,® 3-Dione Hiv-1 Inhibitors Who Have Displays Strategic Nanomolar Cytotoxicity-JuniperPublishers

Journal of Chemistry-JuniperPublishers

Abstract

Model speeds drug discovery a series of novel, twenty 1,3,5-tri substituted-lH- indole 2,3-dione scaffold on a putative "U shape" molecular recognition of novel HIV-1 inhibitors were designed and synthesized using a parallel synthesis unit processes technology. Among synthesized and tested compounds 1A, 1B, 1C, 1D, 1E, 1F, 1G and 1H found good quality of IC50 ranges from 4.91 to 32.01μg. One among those, compound 1C is the most potent inhibitor as a target compound against HIV-1. Target compound N-[(3Z) 5-methoxy-1-(morpholin-4-ylmethyl)-2-oxo-1,2-dihydro- 3H-indol-3ylidene]amino}benzene sulfamethaxazole (1C) tactically very low cytotoxicity (CC50>1mM). It is reported 7.15 μg/ml to engineered cell lines, TZM- l (JC53BL-13).

Keywords: N-[(3Z) 5-methoxy-1-(morpholin-4-ylmethyl)-2-oxo-1,2-dihydro-3H-indol-3ylidene]amino

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Introduction

A human immunodeficiency virus strains is sloppy in its reproduction. However, due to the infidelity of HIV-1 during replication, the emergences of mutations (especially K103N and Y181C) rapidly develop resistance and high cytotoxicity rate to the first-generation with rigid structures, such as Nevirapine (NVP) and Efavirenz (EFV) [1-3]. In an effort to address the low resistance barrier issue, next generations have been designed with the structural feature of smaller building blocks, representative second generation improved drug resistance profiles are the recently marketed diarylpyrimidine analogues rilpivirine (TMC278, RPV) and etravirine (TMC125, ETR) [46]. At this moment, doing up about untapped chemical space in inhibitors binding pocket, also explore unresolved chemical modification obtaining more potent, quality, efficacy and safety back -up extraordinary series of unique 1,3,5 tri substituted- 1H-indole-2,3-dione connected by flexible linkers have been investigated.

Compounds and Reagents

Compounds were authorized from Sigma-Aldrich Company (MO,USA) and structure, compounds, HIV activity were amplified using Biqualys offers accurate analyses combining LC-SPE-NMR- MS and Agilent Cary 630 FTIR spectrometer, Luminometer for virus counts and ELISA analyzer.

Cells and Viruses

Engineered TZM-bl indicator cell line was provided by the TZM-bl NIH AIDS Reagent Program USA. This is a CXCR4-positive HeLa cell clone that was engineered to express CD4 and CCR5. Laboratory adapted strains, including HIV-1UG070, 7th PID dated 05/12/14 was obtained from the Department of Molecular Virology, Bio safety Laboratory -II NARI Pune. An automated, 96-well parallel array synthesizer for solid-phase organic synthesis has been designed and constructed. The instrument employs a unique reagent array delivery format, in which N-morpholinomethyl-indole-2, 3-dione utilized has a dedicated plumbing system. An inert atmosphere is maintained during all phases of a synthesis, and temperature can be controlled via a thermal transfer plate which holds the injection moulded reaction block. The reaction plate assembly slides in the X-axis direction, while eight nozzle blocks holding the glacial acetic acid reagent lines slide in the Y-axis direction, allowing for the extremely rapid delivery of sulphonamide reagents to 96 wells. In addition, there are six banks of fixed nozzle blocks, which deliver the same reagent or solvent to eight wells at once, for a total of 72 possible reagents. The system described herein is an efficient means for the parallel synthesis of compounds for lead.

Interpretation of Gold Dock

A computer program designed to screen rapidly by performed using Gold Dock Suite. The coordinates for X-ray crystal structure of HIV-1 (PDB code: 3M8Q) was downloaded from the Protein Data Bank (PDB) at the Research Collaboration for Structural Bioinformatics (http://www.rcsb.org/pdb/home/ home.do) and Shanghai small molecular database (SSMD) has been utilized. Gasteiger charges were assigned to both protein and ligands. A grid with spacing of 0.375 A and 60x60x60 points in the x, y, and z axes was built and centred on the centre of mass of the bound ligand in the crystal structure. Energy grid maps for all ligand atom types were calculated, while keeping the protein structure rigid, we selected Lamarckian genetic algorithm (LGA) to search the conformational and orientation space of the ligands. Each small molecule, 100 separate docking calculations were performed with the breakpoint settings of parameters: population size of individuals at 350, a maximum number of 25 million energy evaluations, a maximum number of generations of at 27,000, a mutation rate of 0.02, a crossover rate of 0.8, and an elitism value of 1. Docking, cluster analysis was performed on the results with the root-mean-square (RMS) deviations less than1.0 A. The breakthrough docked conformation was then selected as the lowest energy stance in the most populated cluster.

Thus, the lowest binding energy complex of more populated cluster depicts more specific and highly reliable, greater efficacy binding conformation of the compound. Insertion of the hydrogen bonding with K101 was constraints for the specificity of binding of compounds in active site of strain as reported in previously. The computational simulation of active compounds showing higher inhibition was compared with that of etravirine, next generation drug. In docking study standard etravirine [a and b ]and compound [1C] showed the hydrogen bonding with K101 residue because the second position C= O group in ring brought to form hydrogen bonding with in hydrophobic pocket of enzyme, in this context C=O is a oxygen isolated in the active compound 1C they formed hydrogen bond with back bone of K101 residue which is crucial for drug resistance and thus compromised the untapped chemical space in IBP and this increase the affinity of compound toward strain inhibition. It is further conclude that region having OCH3, Br, CH3, Cl of C-5 and distance between interaction 2.44 and combined K103, prone to mutation at the IBP entrance. Like pyrrole ring substitution on C-1 by morpholine showed higher activity as it has made vander walls force that are acting upon TYR 188 with distance 3.307 between residue atom and ligand atom which going to stabilized the inhibitor binding pocket and it should be prevent the inhibitor from leaving the binding pocket. Vander walls force interaction act on TYR 188 which made flexible clamp, however mutation resulting in looses or any changes interaction (Figure 1).

Most important in this research and finding substitution at C-3 by sulphonamide based substituent�s may be lead pi-pi stacking interaction between compound and aromatic amino acid residue TYR 181 with interaction distance 5.9 which is prone to mutation resulting loss or change of interaction. This clearly indicates that the inhibitor binding process and residues must facilitate to enter the binding pocket and adopt an appropriate conformation is the optimal interaction with the surrounding residue. This lead to change due to conformation of U, shoes horse like structure, made sites feedback inhibitor to regulate the activities and showed higher activity. Legend: black dashed line-hydrogen bond, salt bridge, metal interaction, green solid line- hydrophobic interaction, green dashed line-pi-pi, pi-cation interaction. Note: Covalent bonds to protein are not displayed. Image generated using pose view software. By downloading this image you confirm to follow citation rule (Figure 2).

3D structure of the docked conformation of target compound, N-[(3Z) 5-methoxy-1 (morpholin-4-ylmethyl) -2-oxo-1,2- dihydro- 3H-indol-3ylidene]amino} benzene sulfamethaxazole (1C) and BP of K103N/Y181C mutant HIV-1 strain, (PDB code:3M8Q),showed interaction of target compound in purple colour and 3M8Q in green and blue colour. Predicted Figure 2C showed the hydrogen bonding with K101 residue, Figure 2D hydrophobic interaction, pi-pi interaction, hydrogen bonds formed between target compound and K101 were maintained which is crucial for drug resistance and (d) merged molecule insertions position in inhibitor-binding pocket (IBP) (PDB:3M8Q) cavity endorsed lock form in open position and stop the transcription.

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Conclusion

A comparison of the designed, synthesized and evaluated novel 1, 3, 5- tri- substituted-1H-indole 2,3-dione which showed nano molar activity against HIV-1. Taste compounds 1A, 1B, 1C, 1D, 1E, 1F, 1G and 1H possess inhibitory activity. Target compound N-[(3Z) 5-methoxy-1-(morpholin-4-ylmethyl)- 2-oxo-1,2-dihydro-3H-indol-3ylidene]amino} benzene sulfamethaxazole (1C) displays potency (IC50 at micro molar level) and detect low cytotoxicity (CC50s > 1mM) against HIV- 1 UG070 7th PID. In this study and model of binding energy complexes determination, characterized and examined selected new series of resistance mutation (refence protein 3M8Q PDB) and noted changes in interaction between target compound and HIV-1 mutant. At best, binding energy could be related to IC50 in assay, more negative of the binding energy results in the formation of stronger complexes belonging therefore when a ligand have a low binding energy its affinity towards the HIV- 1 target is bigger also points to the fact that target compound belonging to adaptable are circulating and giving rise to new. The detection of binding energy value of refence protein and reference ligand complexes shows -12.43 kcal/mol and average of experimental binding energy values of new ligands and refence protein complexes were shows -11.60 kcal/mol. Target compound [1C] has been shown binding energy -8.69 kcal/ mol, which was show its affinity towards the protein 3M8Q is sizeable in comparison with other lead ligands with higher binding energy. IC 50 of target compound N-[(3Z) 5-methoxy-1- (morpholin-4-ylmethyl)-2-oxo-1, 2-dihydro-3H-indol 3ylidene] amino} benzene sulfamethaxazole (1C) was found to be 4.91 μg/ ml. Also it has been clearly indicates strain- target compound inhibitor binding energy values highly correlated which is less than two reported determined binding energy values, which is high degree to cover all edges and outskirt in IBP and reduce the frequency of chemical space creation.

The differences in these correlations may reflect good ground of biological features of the interactions of HIV-1 inhibitor and its complexes. A thorough study was carried out over twenty computationally designed 1,3 5- tri substituted- 1H-2,3-dione analogs using gold dock suite and program with the goal of identifying potential lead molecules that bind to the HIV -1 mutant protein respectively. The comparatively higher interaction scores of lead compounds compared to Etravirine when docked with HIV-1 mutant protein at the IBP active site residue suggest these novel leads would potentially bind more strongly to the pockets of HIV -1 3M8Q proteins. Further, the leads are docked with Lys101, Val106, Leu234 and His235 this proteins residue to predict their binding efficiencies with HIV-1 protein. All the twenty designed 1,3,5- substituted-2,3-dione and its analogs with chemical substitutions at the X1,X3,X5 showing better interactive scores respectively than reference ligand ( Interactive score = -152.57), as a result of docking of among twenty analogs eight lead compounds 1A,1B,1C,1D,1E,1F,1G and 1H were shows interactive score -81.69, -88.28, -80.98, -55.92, -85.35, -74.04, -67.87 and -78.17 and in-vitro experiment IC 50 were found 25.65μg/ml, 31.18μg/ml, 4.91μg/ml, 32.01μg/ml, 4.59 μg/ml, 3.96 μg/ml, 5.02 μg/ml and 25.34 μg/ml. To date the target molecule 1C, when docked with 3M8Q, have shown better dock scores (Interaction Score -80.98 compared to reference ligand (Interaction Score -152.57). Hence these are expected to bind strongly onto inhibitor binding pockets and have suggested that above is highly functional novel lead has very low cytotoxicity (CC50>1mM) and it has been displays 7.15 μg/ml to cell lines, TZM-bl and displayed potent anti-HIV-1 activity found 4.91 μg/ ml against laboratory adapted strains UG070, 7th PID. Ethics statement, the study was conducted in accordance with basic principal and study of the Bio safety Laboratory II and Bio safety Laboratory III, National AIDS Research Institute (ICMR) Pune. This study and the informed consent processes were approved by the Indian Council of Medical Research Government of India.

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Acknowledgment

I would like to express deep gratitude to my post-doctoral guide Renowned Scientist, Respected Dr. Ramesh S. Paranjape Retired Director & Scientist 'G' National AIDS Research Institute, India.

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gyrlversion · 5 years

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MPs reject all FOUR alternatives for Brexit

MPs have again voted down all alternative Brexit options put to it in a second of votes aimed at finding a replacement for Theresa May’s Brexit deal.

The Commons tonight rejected a customs union, Norway-style soft Brexit, second referendum and cancelling Brexit.

The customs union plan proposed by Ken Clarke was closest to victory – losing by just three votes 276 to 273. A second referendum got the most votes overall for a second week, with 280 votes to 292 against.

Tory MP Nick Boles sensationally resigned from his party and crossed the floor moments after the votes were announced – blaming the Conservatives refusal to compromise for the failure to find a way forward. His plan for a Norway-style soft Brexit was defeated 282 to 261 – having won just 33 Tory votes.

In what may become an historic moment during the Brexit crisis and on the brink of tears, Mr Boles admitted his plan to find a consensus had ‘failed’ and announced he could no longer stay in the party.

An SNP-inspired plan to revoke Article 50 to avoid No Deal was the most heavily defeated. It lost 292 to 191.

The votes were staged after rebel MPs seized control of the Commons agenda in the wake of Mrs May’s deal being repeatedly trounced. After the votes were called, Brexit Secretary Stephen Barclay warned MPs had still not voted for a clear way forward and confirmed the Cabinet would discuss the outcome tomorrow.

Earlier, the debate was interrupted by semi-naked protesters in the public gallery.

Mrs May has summoned her ministers to an epic Cabinet tomorrow – fuelling speculation she is getting ready for the ‘nuclear’ option of an election despite her deep unpopularity in her own party.

Instead of the usual 90-minute discussion, Tory ministers will spend three hours locked in talks without officials from 9am – meaning they can discuss party politics and how to tackle the Brexit endgame in light of the results.

There will then be a normal two-hour Cabinet where the Government can take decisions on the fate of the nation.

Mr Boles said: ‘I have given everything to an attempt to find a compromise that can take this country out of the European Union while maintaining our economic strength and our political cohesion.

‘I accept I have failed. I have failed chiefly because my party refuses to compromise. I regret therefore to announce I can no longer sit for this party.’

One MP could be heard saying: ‘Oh Nick, don’t go, come on.’

Independent Group leader Heidi Allen said she did not know Mr Boles was going to quit the Tories but said he was welcome to join their new group.

Feuding MPs were told to vote on four alternatives to Theresa May’s (pictured returning to the Commons this evening) Brexit deal tonight amid fevered speculation she could force an election to end the impasse

Tory MP Nick Boles sensationally resigned from his party and crossed the floor after the votes were announced – blaming the Conservatives refusal to compromise for the failure to find a way forward

Speaker John Bercow selected proposals for a customs union, Norway-style soft Brexit, second referendum and cancelling Brexit in the second round of indicative votes tonight

MPs voted on pale blue ballot papers containing four different motions for alternative Brexit plans. Craig Mackinlay revealed he voted for none of them

Most Tory MPs had a free vote on the alternatives to Mrs May’s deal tonight, with 25 or more junior ministers predicted to be ready to back a softer Brexit.

Cabinet ministers have been told to abstain, but, with a growing rift between Remainers and Brexiteers in the Government, some could still choose to vote for a customs union and resign.

All eyes will be on the 10 ministers known to back a customs union with the EU if Theresa May’s deal is killed off, including the ‘gang of four’ cabinet remainers: Work and Pensions Secretary Amber Rudd, Justice Secretary David Gauke, Business Secretary Greg Clark and Scottish Secretary David Mundell. They would be willing to quit if Mrs May pushes for a No Deal Brexit and could do it by defying her order to abstain in tonight’s indicative votes.

But Tory Brexiteer Jacob Rees-Mogg today admitted he is ‘very concerned’ that Theresa May will add a customs union onto her Brexit deal to get it through Parliament.

He told LBC radio: ‘My concern is that the Prime Minister is more concerned to avoid a No Deal Brexit than anything else. And therefore I am very concerned that she could decide to go for a customs union tacked onto her deal.’

Mr Rees-Mogg also claimed that last Friday’s vote on the Brexit deal would ‘probably have gone through’ if it had been Mrs May’s deal versus a general election.

Semi-naked climate change protesters interrupted the Commons debate on Brexit alternatives tonight as they stripped off in the public gallery

Tory MP James Heappey defied Commons rules to photograph the dozen people, one of whom had ‘climate justice now’ daubed on his back

MPs to vote on a customs union, soft Brexit, a second referendum or cancelling Brexit

None of the eight alternatives to Prime Minister Theresa May’s deal were approved last week after Parliament seized control of the Commons agenda.

Commons Speaker John Bercow has whittled them down, and is putting four rival Brexit plans to the Commons tonight. He selected a UK-EU customs union, soft Norway-style Brexit, second referendum and cancelling Brexit.

Ahead of the second round, the customs union and second referendum were the leading options.

Motion C: Customs union with the EU

Tory former chancellor Ken Clarke’s customs union plan requires any Brexit deal to include, as a minimum, a commitment to negotiate a ‘permanent and comprehensive UK-wide customs union with the EU’.

This is where tonight’s vote could get interesting. This amendment last week lost by the tightest margin of them all.

It went down by eight votes, losing by 272 to 264. It means that a handful of MPs changing their mind could see it across the line.

But the SNP and Lib Dems abstained last time so those votes may not be easy to find on the polarised Tory and Labour benches.

And it if did win it would cause havoc in the Government with Brexiteers going on the warpath.

Motion D: Common market 2.0 – Norway-style soft Brexit

A cross-party motion tabled by Conservatives Nick Boles, Robert Halfon and Dame Caroline Spelman and Labour’s Stephen Kinnock, Lucy Powell plus the SNP’s Stewart Hosie.

The motion proposes UK membership of the European Free Trade Association and European Economic Area. It allows continued participation in the single market and a ‘comprehensive customs arrangement’ with the EU after Brexit – including a ‘UK say’ on future EU trade deals – would remain in place until the agreement of a wider trade deal which guarantees frictionless movement of goods and an open border in Ireland.

Despite Labour backing last week this lost by almost 100 votes, 283 to 188. But 167 MPs abstained on it, including the DUP. If the Northern Irish party could be talked in to backing it there could be some movement.

Motion E: Second referendum to approve any Brexit deal

Drawn up by Labour MPs Peter Kyle and Phil Wilson, this motion would require a public vote to confirm any Brexit deal passed by Parliament before its ratification.

This option, tabled last time by Labour former minister Dame Margaret Beckett, polled the highest number of votes, although was defeated by 295 votes to 268.

Labour MPs were whipped to support it but 27 mainly from northern Leave-voting areas voted against it and a further 18 – including several frontbenchers – abstained.

Their support would have been enough to pass it but it seems unlikely they will change their minds, given that their concerns remain the same.

Motion G: Revoke Brexit to avoid No Deal

SNP MP Joanna Cherry joins with Mr Grieve and MPs from other parties with this plan to seek an extension to the Brexit process to allow Parliament and the Government to achieve a Brexit deal.

If if this is not possible then Parliament will choose between either no-deal or revoking Article 50.

An inquiry would follow to assess the future relationship likely to be acceptable to Brussels and have majority support in the UK.

Senior ministers have warned the Prime Minister she would ‘destroy’ the Tory party and put Jeremy Corbyn in Downing Street if she gives in to demands to adopt a soft Brexit.

If she were to give way to a softer Brexit, Mrs May would provoke a furious reaction from Brexiteers, with International Development Secretary Penny Mordaunt and Transport Secretary Chris Grayling among the ministers reportedly ready to resign.

But more than 170 Tory MPs, including 10 Cabinet ministers, have already signed a blunt, two-paragraph letter to Mrs May reminding her of the party’s manifesto commitment to take Britain out of both the customs union and the single market.

The letter urges her to take the UK out of the EU without a deal on April 12 if she cannot get her own deal through Parliament in the coming days.

Today Chief Secretary to the Treasury Liz Truss said: ‘I don’t have any fear of No Deal – what would be worse is if we don’t Brexit at all’.

But, fuelling expectations Mrs May will try a fourth vote on her deal, she said: ‘I think the answer lies in modifications to the Prime Minister’s deal to be able to get that to have support.’

She also warned the PM against lurching towards a customs union deal because ‘it’s not clear that going softer is the way to command support’ – but ruled out quitting.

Labour is to support the Common Market 2.0 option for Brexit (participation in the single market and a ‘comprehensive customs arrangement’ with the EU including a ‘UK say’ on future EU trade deals) in Monday’s indicative votes in the House of Commons, as well as other options which the party backed last week: a customs union and a second referendum on any deal.

The Common Market 2.0 plan would not end freedom of movement from the EU.

Jeremy Corbyn’s decision is expected to push one or more of these indicative votes over the line tonight.

A Labour spokesman said: ‘In line with our policy, we’re supporting motions to keep options on the table to prevent a damaging Tory deal or No Deal, build consensus across the House to break the deadlock and deliver an outcome that can work for the whole country’.

Mrs May’s deal has now fallen three times in the Commons, with dozens of Tory MPs among those who voted against it on each occasion.

Today Conservative backbencher Richard Drax apologised for backing her EU divorce on Friday.

The South Dorset MP said he should have trusted his instincts ‘and those of the British people’ when he voted on the withdrawal agreement on Friday.

Addressing the House of Commons, Mr Drax said: ‘I made the wrong call on Friday’.

He added: ‘If the Prime Minister cannot commit to taking us out of the EU on April 12, she must resign immediately.

‘This is no longer about leave or remain. That was decided in 2016. This is about the future of our great country.’

DUP Brexit spokesman Sammy Wilson also claimed his party will reject her deal even if it was brought back to the Commons ‘a thousand times’.

He said: ‘As far as the Withdrawal Agreement is concerned and the motion before us is concerned, our position has not changed.

‘We have sought to, over the last number of weeks, work with the Government to try and find a way of either getting legal assurances or legislative changes which would enable us to move this process on – we want to see a deal because we want out of the European Union, and we want to have a clear path as to how we do that.

Mrs May (pictured today arriving at Downing Street) could face resignations across the Cabinet after the Brexiteer and remainer factions hardened their stances

Boris Johnson, pictured cycling to Parliament today, and Michael Gove, pictured leaving home today are the two favourites to replace Theresa May when she leaves No 10

Timetable for four days of Westminster turmoil

Today: MPs led by Tory Sir Oliver Letwin and Labour’s Yvette Cooper will vote tonight on whether to adopt a soft Brexit option, such as a customs union or membership of the single market, possibly accompanied by a second referendum. Last week, MPs rejected all eight Brexit options put to them in a series of ‘indicative votes’, but supporters of a soft Brexit from both the Tory and Labour benches believe they have a better chance tonight following the third defeat for Theresa May’s deal.

Tomorrow: The Cabinet will meet to discuss a response to the votes. If MPs have backed a customs union, Mrs May will have to decide whether to accept a policy opposed by the vast majority of Tory MPs. If she agrees, the issue could tear the party apart. If she refuses, it would result in a constitutional stand-off that could spark an election. Downing Street fears that she could face a Cabinet walkout regardless of what she decides.

Wednesday: Sir Oliver Letwin has indicated he will try to seize control of the Commons agenda again to pursue his soft Brexit plan. If Monday’s votes were inconclusive, they could be held again, possibly using preferential voting to reduce the options to one. If Monday night’s vote produced a solution, but Mrs May refused to adopt it, Parliament could legislate in a bid to force her hand.

Thursday: Allies of the PM have the day pencilled in for a possible fourth attempt to get her deal through the Commons. They believe that, with the majority against her coming down from 230 to 149 then to 58 last week, they have momentum on their side. Ministers are considering an unprecedented parliamentary ‘run off’ pitting Mrs May’s deal against the soft Brexit option chosen by MPs in the hope of focusing the minds of Tory eurosceptics.

‘But it has not been possible… because the Withdrawal Agreement itself so ties the hands of this Government that it is impossible to find a way of securing the kind of assurances which are required to make sure the United Kingdom is not broken up, and that we do have a clear way of ensuring that the Brexit which many of us expected to see delivered would be delivered.

‘It’s our regret that that process has reached an end.’

Environment Secretary Michael Gove said today: ‘One thing is clear: We have to leave the European Union in good order. Parliament won’t vote for No Deal. No Deal is bad for our economy and bad for our union’.

Last night, two Cabinet ministers told the Daily Mail that shifting to a soft Brexit could lead to a collapse of the Government and usher in a Labour regime led by Mr Corbyn.

One said: ‘If forced to choose I would favour a general election over a customs union, but it’s like a choice between being stabbed in the left hand and stabbed in the right. Either one could take us to a Corbyn government.

‘The Conservative Party cannot accept a customs union, and at least half the Cabinet won’t accept it. It would destroy the party and it would lead to an election anyway, which we would then lose.

‘The only route we can possibly survive is to go for No Deal. At least we would then enter an election in the right political place, having delivered Brexit.’

Another Cabinet minister said: ‘We cannot go for a customs union – there would be no government left. And if we go for an election then Corbyn will be likely to win and we would end up with a customs union anyway.’

Justice Secretary David Gauke infuriated Eurosceptic MPs yesterday when he declared that Mrs May would have to ‘look closely’ at adopting a customs union if Parliament votes for it.

Pro-EU demonstrators resumed their daily campaign outside the Palace of Westminster today as MPs convened for another week of wrestling with Brexit

The streets outside Parliament have been packed with campaigners on both sides of the Brexit divide for months

Meanwhile Boris Johnson urged the Tories to ‘believe in Britain’ and ‘get Brexit done’.

Writing in the Daily Telegraph, he said: ‘We should really come out with no deal – now looking by far the best option.

‘But if we cannot achieve that, then we need to get out, now, with an interim solution that most closely resembles what the people voted for, in the knowledge that – following the Prime Minister’s decision to step down – we have at least the chance to fix it in the second phase of the negotiations.’

Mr Gauke and fellow Remainers Greg Clark, Amber Rudd, Philip Hammond and David Lidington are urging Mrs May to push for a softer Brexit if it avoids No Deal.

Last night, members of the group were privately encouraging Remainer Tories to back the option in tonight’s vote.

But Downing Street slapped down Mr Gauke, saying Mrs May was committed to delivering a Brexit deal ‘which does not include membership of the custom union’.

However, a pro-Remain Cabinet source said Mrs May would have to accept the will of Parliament, adding: ‘Something is going to have to give this week – she is finally going to have to pick a side, and that is going to leave one half of the Cabinet very unhappy. But if the majority in Parliament comes out for a customs union then that will be very hard to resist.’

Tory Brexiteer Jacob Rees-Mogg has said he is ‘very concerned’ that Theresa May will add a customs union onto her Brexit deal

At the start of another dramatic Brexit week:

Government sources said Mrs May would try to bring her deal back to the Commons for a fourth time this week, despite hopes fading that the DUP will ever support it.

Before any fourth vote on the deal, a new round of indicative votes will be held on alternatives in the Commons tonight.

European Commission president Jean-Claude Juncker said: ‘We have had a lot of patience with our British friends over Brexit but patience runs out.’

Tory deputy chairman James Cleverly warned that Mrs May could lead the party into a snap general election if the Brexit deadlock continues, despite opposition from Tory MPs and a poll putting Labour five points ahead.

Work and Pensions Secretary Mrs Rudd set up a new group of moderate Tories designed to block hard Brexiteers such as Dominic Raab and Boris Johnson succeeding Mrs May as PM.

UK boss of Siemens claims that Britain is now a ‘laughing stock’ over Brexit as he warns that Theresa May must avoid ‘hugely damaging’ No Deal

Britain is becoming a ‘laughing stock’ over Brexit and risks leaving the trading bloc with a hugely damaging No Deal, the UK head of German industrial giant Siemens has said.

After Prime Minister Theresa May‘s Brexit deal was rejected by parliament for a third time last week there is pressure from rival factions for a no-deal exit, a much softer divorce or an election.

Juergen Maier said today: ‘Where the UK used to be beacon for stability, we are now becoming a laughing stock.

‘It has been clear for weeks, that the only way that this will be resolved is through compromise between the government and parliament’.

Maier said it was becoming hard for him to win support from his board for investment decisions as Britain heads towards a ‘hugely damaging No Deal Brexit.’

‘Enough is enough. We are all running out of patience. Make a decision and unite around a customs union compromise that delivers economic security and stability,’ he said in a letter to Politico.

In other developments today, Mrs May’s Commons enforcer has criticised the Government’s approach to leaving the EU and said his party should have made it clear a ‘softer Brexit‘ was ‘inevitable’ after the 2017 election.

In an extraordinary interview Julian Smith, the Tory chief whip, also and attacked Cabinet members over the ‘worst example of ill-discipline in British political history’.

He said ministers have been ‘sitting around the Cabinet table trying to destabilise her (Mrs May)’, revealing the battle the Prime Minister has with both Brexiteer and remainers in her Cabinet.

It came as MPs are set to take back control of the Brexit agenda in a fresh attempt to find an alternative to Theresa May’s deal that Parliament can support.

The Commons will stage a second round of ‘indicative’ votes on Monday on a series of rival proposals tabled by backbenchers to see if any can command a majority.

The move comes as Mrs May struggles to contain the rising tensions with her Cabinet as the clock counts down to the latest EU deadline on April 12.

If she were to give way to a softer Brexit, she would provoke a furious reaction from Brexiteers, with International Development Secretary Penny Mordaunt and Transport Secretary Chris Grayling among the ministers reportedly ready to resign.

Mr Smith spoke out to suggest ministers had pursued the wrong strategy after the Prime Minister lost the Conservatives’ Commons majority in the 2017 snap election.

He said the result of the poll meant that Mrs May simply did not have enough MPs to back a harder version of Brexit.

‘Brexit is a sh**show’: German minister hits out at the chaos in Westminster and ‘out-of-touch’ Cabinet ministers

Michael Roth lashed out at UK politicians at an event in berlin on Saturday

Brexit has been branded a ‘big s**tshow’ by a top German politician who likened it to a Shakesperean tragedy as Westminster continued to be gripped by total chaos.

Berlin‘s Europe minister Michael Roth made the pithy assessment as he blasted Theresa May‘s Cabinet of being out of touch with the people, admitting that he was speaking ‘very undiplomatically’.

He told a meeting of the Social Democratic Party in Berlin on Saturday that 90 per cent of Theresa May’s top ministers had ‘no idea how workers think, live, work and behave’, Bloomberg reported.

He also lashed out at politicians ‘born with silver spoons in their mouths, who went to private schools and elite universities’ who would not suffer as a result of any messy Brexit.

According to Bloomberg he said: ‘I don’t know if William Shakespeare could have come up with such a tragedy but who will foot the bill?’

In a sign that patience is wearing very thin on the Continent the European Parliament’s Brexit co-ordinator Guy Verhofstadt today described Brexit as a ‘tragic reality’ and urged MPs to find a compromise in Monday evening’s votes.

He tweeted: ‘Brexit is not a bad April Fool’s Joke, but a tragic reality for all our citizens and business.

‘It is now five to midnight. Today MPs must find a compromise & stop this chaos.

‘This evening, for once voting ‘Yes’, instead of every time voting ‘No’.’

The comments were published by the BBC amid speculation that Parliament may force the PM to seek membership of a customs union with Brussels in order to pass her deal, which would mean ripping up one of her key red lines.

‘The thing that people forget is that the Conservative Party went to get a majority in order to deliver Brexit (and) failed to get a majority,’ the chief whip said.

‘The Government as a whole probably should just have been clearer on the consequences of that. The parliamentary arithmetic would mean that this would be inevitably a softer type of Brexit.’

While the strategy was apparently misjudged, Mr Smith said he was ‘frustrated’ by MPs who ‘don’t see the light as clearly as I do’.

Mrs May’s deal has now fallen three times in the Commons, with Tory MPs among those who voted against it on each occasion.

However Mr Smith highlighted that a lack of discipline extended all the way to the Cabinet, with ministers ‘sitting around the Cabinet table … trying to destabilise her (Mrs May)’.

‘This is I think the worst example of ill-discipline in Cabinet in British political history,’ he said.

Later tonight, MPs will launch a fresh attempt to force Theresa May into a soft Brexit tonight by holding a second round of indicative votes on alternatives to her deal.

Ministers believe as many as 70 Tory MPs could add their support to a proposal to remain in the EU customs union. It lost by just six votes in a first indicative vote last week, meaning extra Tory support could see it win a majority of MPs.

Backbenchers led by Sir Oliver Letwin have taken control of the Commons timetable to stage a second round of indicative votes after none of the eight options put to MPs last week won enough support.

If a majority emerges for one of the alternatives tonight, the rebels plan to put down legislation on Wednesday that would force ministers to act.

Former Cabinet minister Ken Clarke, who drew up the customs union plan defeated by just six votes last week, has said he is ‘reasonably confident’ it will get over the line this time.

No Deal vs Customs Union: How Cabinet ministers stand

For a No Deal

Sajid Javid

Stephen Barclay

Michael Gove

Chris Grayling

Penny Mordaunt

Andrea Leadsom

Liz Truss

Alun Cairns

Liam Fox

Gavin Williamson

Brandon Lewis

James Brokenshire

Geoffrey Cox

Source: Daily Telegraph

For a customs union

Amber Rudd

Greg Clark

David Lidington

Philip Hammond

David Gauke

David Mundell

Claire Perry

Caroline Nokes

Damian Hinds

Karen Bradley

Not declared

Matt Hancock

Jeremy Wright

Jeremy Hunt

Source: Daily Telegraph

Meanwhile, supporters of a so-called ‘Common Market 2.0’ proposal that would keep Britain in the customs union and the single market have been seeking to win over DUP and SNP MPs who all abstained when it was voted on last week.

Staying in the single market would involve continued freedom of movement and making contributions to the EU budget, while being in a customs union would prevent Britain from striking its own trade deals.

Nick Boles, the Tory ex-minister behind Common Market 2.0 – rejected by 283 votes to 188 last week – declared last night that it was ‘alive and squawking’.

‘The only reason it scored fewer votes overall was that Labour didn’t whip for it. Tomorrow that might change,’ he said.

Tory George Freeman, who backs the idea, said: ‘Only Common Market 2.0 looks like winning support from all parties.’

The SNP’s Westminster leader Ian Blackford said his party’s 35 MPs would not back Mr Clarke’s plan as it would end freedom of movement, but signalled that they could back Common Market 2.0 because they want single-market membership.

Downing Street is considering offering a run-off between Mrs May’s deal and the frontrunner from the indicative votes.

Despite three previous rejections, No10 believes her deal could still prevail because in the first round of the indicative votes on Friday it did better than any alternative.

In an article for Conservative Home, Tory ex-minister Greg Hands yesterday warned that staying in the customs union would be a ‘serious mistake’ and ‘in the medium term be democratically unsustainable’.

Boris Johnson makes his first pitch to be Tory leader as a senior minister says the party needs an ‘experienced Brexiteer’ at the helm when Theresa May quits

Boris Johnson today made his first public pitch to succeed Theresa May, as senior Tories called for an experienced Brexiteer to take over.

Days after he finally backed the Prime Minister’s deal, Mr Johnson said a No Deal exit is ‘far the best option’ and insisted the Conservatives should ‘get on with it’.

And in his own vision for the party he said the Tories should then concentrate on ‘cutting taxes wherever we reasonably can’, including stamp duty and inheritance tax.

It came as Transport Secretary Chris Grayling said it was ‘more likely than not that the next leader will be someone who campaigned for Brexit‘.

Boris Johnson (pictured today) has three times the support of his closest rival in leadership polling and made his first pitch to be leader today

Mr Johnson, who has been accused of disloyalty for his opposition to Mrs May’s deal, wrote in the Telegraph today: ‘We cannot go on like this. We need to get on with it and to get it done. We should really come out with No Deal – now looking by far the best option; but if we cannot achieve that, then we need to get out, now.

‘We need to get Brexit done, because we have so much more to do, and so much more that unites the Conservative Party than divides us. We have so many achievements to be proud of – and yet every single one is being drowned out in the Brexit cacophony’.

Chris Grayling has called for an ‘experienced’ Brexiteer to take over the party – seen as a nod towards Mr Johnson rather that his rival Dominic Raab.

He told the Telegraph: ‘The party has to ask itself a question about the leadership: the next two or three years are going to be very tough because the European stuff is not going to go away.

‘Is the person who takes us through the next two or three years and sorts out Brexit and gets the sort of hard time that Theresa has had, the same person who we want to be leading us into the 2027 general election?

‘It may be that we are planning two things rather than one. Planning somebody who has got the experience and resilience to get us through the immediate future. But then … we have got a really good generation of younger politicians in their 40s who can make a real impact, who are going to be the leadership of the party in the future.’

Moderate Tories appeared to step up efforts to frustrate the leadership ambitions of Boris Johnson last night, launching a new grouping opposed to a No Deal Brexit.

Around 40 MPs have signed up to the One Nation Group which will be led by Work and Pensions Secretary Amber Rudd and former education secretary Nicky Morgan.

The faction, which is aiming to be a counterweight to the European Research Group, is planning to host its own hustings in any future party leadership contest and has ruled out supporting anyone who wants a No Deal departure.

Mr Johnson, however, did get some backing from an unlikely quarter last night – Tony Blair.

The former PM claimed the Tories could beat Labour in a general election if ‘formidable’ Mr Johnson was leader.

Amber Rudd is relaunching the One Nation faction inside the Tory party as moderates move to block Boris Johnson and hard Brexiteers in the race for power

As ministers fight for the job Liz Truss (left in Westminster on Friday) today called for the Tory party to remodernise, while Dominic Raab published his plans to tackle knife crime

Jeremy Hunt is seen as a safe pair of hands and could help unite the party, some MPs have claimed

High profile members of the One Nation Group also include Business Secretary Greg Clark, Justice Secretary David Gauke, Scottish Secretary David Mundell, energy minister Claire Perry, as well as Damian Green and Sir Nicholas Soames.

Sir John Major yesterday criticised potential leadership candidates for jockeying for position instead of focusing on attempts to get the Brexit deal passed.

2,000 viewers complain after Jon Snow said ‘I’ve never seen so many white people in one place’ as he covered Brexit rally

Channel 4 has been forced to apologise after news anchor Jon Snow, 71, said he had ‘never seen so many white people in one place’ while reporting on a pro-Brexit rally

Channel 4 News host Jon Snow’s remark that he had ‘never seen so many white people in one place’ has sparked more than 2,000 complaints.

The veteran 71-year-old presenter was signing off from Friday evening’s Channel 4 News bulletin when he made the controversial comment.

He was referring, during the live broadcast, to the pro-Brexit protesters who brought Westminster to a standstill.

‘It’s been the most extraordinary day,’ he said. ‘A day which has seen … I have never seen so many white people in one place, it’s an extraordinary story.

‘There are people everywhere, there are crowds everywhere.’

Broadcasting watchdog Ofcom said it had received 2,025 complaints and is deciding whether to investigate.

The high level of objections to the comment would place the show as the fifth most complained about, when compared to the numbers from Ofcom’s most complained about shows in 2018.

The show which drew the most complaints was Celebrity Big Brother (27, 602), followed by Loose Women (8,002), Sky News (4,251), Love Island (4, 192).

The next on the list is Coronation Street, but that only has 1,098 complaints compared to Jon Snow’s 2,025.

He told the BBC’s Andrew Marr programme: ‘I think they should concentrate on the decision we should make next week, not who is going to be prime minister at some future stage.’

Sir John appeared to criticise hopefuls such as Mr Johnson, Esther McVey and Dominic Raab, who last week backed Mrs May’s Brexit deal despite making dire warnings about it.

‘I find it extraordinarily odd that there are people who decided the Prime Minister’s deal was going to turn us into a vassal state and they voted against it. Once it is apparent there’s going to be a leadership election and one of them might become prime minister, the question of a vassal state disappears and they support it,’ he said. ‘I think the public will be very cynical about that.

‘I don’t know when the Prime Minister will go and nobody can be certain… but when we elect a new prime minister I think it has to be someone who can be a national leader, not a factional leader and I think that does disqualify a number of candidates.’

Sir John also said the UK will always have a centre-Right party and a centre-Left party, adding: ‘Whether that’s exactly the same Conservative Party as we have now or not, I can’t be certain – but that there will be a Conservative Party on the centre-Right of politics, but it needs to be at the centre-Right if it wishes to win, not the far-Right.’

Several senior Tories yesterday appeared to be on manoeuvres to replace Mrs May this weekend.

Liz Truss, Chief Secretary to the Treasury, called for the Conservative party to ‘remodernise’ as she set out her stall in a newspaper interview. Miss Truss, who backed Remain in the referendum and was previously in charge at the Ministry of Justice and Defra, picked out cutting taxes for businesses and stamp duty for young home buyers as key policies.

She told The Sunday Times: ‘Sometimes politics can be in danger of being managerial. The Conservative Party needs to remodernise. We need to be optimistic, aspirational. We need to participate in the battle of ideas. We haven’t been doing.’

Other Cabinet ministers tipped to join the race when the time comes include Environment Secretary Michael Gove, Foreign Secretary Jeremy Hunt, Work and Pensions Secretary Miss Rudd, Home Secretary Sajid Javid and House of Commons leader Andrea Leadsom. Mr Johnson, Miss McVey and Mr Raab, who all quit the Cabinet in protest at Mrs May’s handling of Brexit, are also expected to go for No 10. Mr Raab, a former Brexit Secretary, yesterday attempted to outflank hostile competition by addressing allegations that he used a non-disclosure agreement, also known as a ‘gagging order’, to silence a former colleague who accused him of bullying.

He told The Sunday Times the claims were ‘completely false’, while his allies suggested they were being deployed as part of a ‘smear campaign’.

Another former Cabinet minister, Justine Greening, said she ‘might’ run for the Tory leadership. In an interview with The Sunday Times, she said the party needed a leader for the ‘2020s, not the 1920s’.

‘It’s 32 years since we had a landslide and we have to answer the question about why we have failed to connect with people and their ambitions,’ she told the paper. Miss Greening, a prominent Remain campaigner, quit as education secretary when Mrs May attempted to make her the work and pensions chief in early 2018.

Mr Blair last night told the HuffPost UK news website that Mr Johnson was a ‘formidable campaigner’ who would pose a powerful challenge to Labour.

‘If you have a Boris Johnson-led Conservative Party, he’s a formidable campaigner, he’s an interesting personality, he can get out there and do his stuff, for sure,’ he said. ‘I have absolutely no doubt if you have a Right-wing populism against a Left-wing populism in this country, the right-wing will win. So it depends where we [Labour] stand.’

Mrs May last week promised to step down if MPs passed her Brexit withdrawal agreement.

And they’re off! From hard Brexiteers to Remainers, the race for No.10

Dominic Raab 10/1

Age: 46. Former Brexit Secretary. Diehard Brexiteer.

Background: Son of a Czech-born Jewish refugee who fled the Nazis in 1938 and died of cancer when Raab was 12.

EXPERIENCE: Lasted only four months as Brexit Secretary. Voted against May in leadership confidence vote.

STRENGTH: Skilled debater who honed his skills as an adversarial lawyer with blue chip legal firm Linklaters.

WEAKNESS: Seen as too clever by half and lacking people skills.

VERDICT: In second place in ConservativeHome’s leadership league table.

Boris Johnson 4/1

Age: 54. Former Foreign Secretary. His support for Brexit was vital to Leave’s win.

Background: Known for being identified by just one name, Boris, for his show-off Classics references and for chaotic private life.

EXPERIENCE: Twice voted London mayor.

STRENGTH: Starry, charismatic and clever crowd-pleaser.

WEAKNESS: Bumbling foreign secretary. May struggle to win MPs’ support. A ‘Stop Boris’ campaign is likely.

VERDICT: Party grassroots love him and he’s top of the ConservativeHome league table by 12 points.

Matt Hancock 25/1

Age: 40. Health Secretary. Arch Remainer.

Background: Father bought their council house. Ran his own computer software business before becoming Chancellor George Osborne’s chief of staff.

EXPERIENCE: Cabinet minister for only 18 months. Seen as a ‘coming man’.

STRENGTH: One of life’s Tiggers with ambition and enthusiasm to match his brainpower.

WEAKNESS: Never knowingly modest, he once foolishly likened himself to Churchill, Pitt and Disraeli.

VERDICT: Little known among Conservative Party members.

Amber Rudd 25/1

Age: 55. Work and Pensions Secretary. Remain cheerleader.

Background: Daughter of a Labour-supporting stockbroker and Tory-leaning JP.

EXPERIENCE: Became Home Secretary after just six years as an MP. Resigned over the Windrush scandal after inadvertently misleading MPs.

STRENGTH: Tough operator who was restored to Cabinet within six months.

WEAKNESS: Holds seat with majority of only 346. Headmisstressy manner but an accomplished performer.

VERDICT: Ninth in leadership league table.

Esther McVey 33/1

Age: 51. Former Welfare Secretary. An ardent Brexiteer.

Background: Spent the first two years of her life in foster care. Was a breakfast TV presenter before becoming a Tory MP on Merseyside.

EXPERIENCE: As welfare minister was viciously targeted by Labour.

STRENGTH: Tough and telegenic. Won plaudits with members for resigning from Cabinet over Brexit deal.

WEAKNESS: Some say she doesn’t have the intellectual fire power for top job.

VERDICT: Ranked 14th in league table.

Penny Mordaunt 33/1

Age: 46. International Development Secretary. Arch Brexiteer.

Background: Her mother died when she was a teenager. Cared for younger brother. EXPERIENCE: Was a magician’s assistant. Appeared in the reality TV show Splash!

STRENGTH: Only female MP to be a Royal Naval Reservist. Attended Lady Thatcher’s funeral in uniform.

WEAKNESS: Inexperienced, having been in Cabinet for less than two years. Has never run a major Whitehall department.

VERDICT: Edged up to 11th in ConservativeHome league table.

Andrea Leadsom 16/1

Age: 55. Leader of the Commons. Ardent Brexiteer.

Background: A former City trader. Mother of three.

EXPERIENCE: Struggled in her first Cabinet post, as Environment Secretary.

STRENGTH: Blossomed as Leader of the Commons, winning plaudits for taking on Speaker John Bercow.

WEAKNESS: Stood for leader in 2016 but made ill-considered comment comparing her experience as a mother to the childless Mrs May.

VERDICT: Has soared to the top of the ConservativeHome table of competent ministers.

Michael Gove 4/1

Age: 51. Environment Secretary. High priest of Brexiteers.

Background: Adopted son of a Scottish fish merchant.

EXPERIENCE: Figurehead for Leave during referendum campaign. Cabinet heavyweight who’s served as Education Secretary and Justice Secretary.

STRENGTH: Brilliant debater with razor sharp intellect.

WEAKNESS: Still suspected of having a disloyal gene after knifing Boris Johnson in last leadership contest.

VERDICT: Popular with the Tory members, who, crucially, will vote for the new leader.

Gavin Williamson 50/1

Age: 42. Defence Secretary. Converted Remainer.

Background: From a Labour-supporting, working class family. Ran a pottery firm before becoming an MP.

EXPERIENCE: Started his rise as Mrs May’s Chief Whip. Leap-frogged experienced colleagues to land defence job.

STRENGTH: Matinee idol looks and knack for self-promotion.

WEAKNESS: Military chiefs nicknamed him Private Pike after Dad’s Army character. Suggested missiles should be fitted to tractors.

VERDICT: In 19th place in league table.

Liz Truss 50/1

Age: 43 Chief Secretary to Treasury. Brexiteer.

Background: Raised by Left-wing parents and as a child was marched through the streets on anti-Thatcher protest shouting: ‘Maggie out!’

EXPERIENCE: Joint-author in 2012 of a controversial booklet, Britannia Unchained, which alleged ‘the British are among the worst idlers in the world’.

STRENGTH: A genuine free-marketeer.

WEAKNESS: Poor public speaker with a mixed ministerial record.

VERDICT: Only 15th in ConservativeHome leaders league table.

Sajid Javid 9/1

Age: 49. Home Secretary. Remainer who changed to Brexit after the referendum.

Background: Son of a bus driver who came to Britain from Pakistan with £1 in his pocket. Was head of credit trading at Deutsche Bank.

EXPERIENCE: Previously Culture and Business secretary, cracked down on union rights.

STRENGTH: An extraordinary rags-to-riches back story that we will hear more of during the leadership campaign.

WEAKNESS: Widely seen as a wooden and a poor speaker.

VERDICT: In 4th place in ConservativeHome league table.

Jeremy Hunt 8/1

Age: 52. Foreign Secretary

Background: Eldest son of Admiral Sir Nicholas Hunt. Married to a Chinese wife and he speaks Mandarin.

Before politics, set up an educational publisher which was sold for £30million in 2017.

EXPERIENCE: Longest-serving health secretary in history.

STRENGTH: Among the most experienced ministers in the field who, unusually, has made few political enemies.

WEAKNESS: Some, though, regard him as a ‘bit of a drip’.

Verdict: Seen by many as man who could best unite party on Brexit.

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