Category Archives: Molecular interactions

PPIs, protein pocket predictions and some endogenous allosteric modulators

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A simplified format for this and likely subsequent blogs from my literature surveys. which I hope you will find useful.  This blog covers a number of topics relating to protein protein interactions

Discovery of Tricyclic Indoles That Potently Inhibit Mcl-1 Using Fragment-Based Methods and Structure-Based Design Jason P. Burke, et al J. Med. Chem., Article ASAP, DOI: 10.1021/jm501984f, Publication Date (Web): April 17, 2015. Copyright © 2015, American Chemical Society

A nice story describing the elaboration of a micromolar tricyclic indole MCL-1 inhibitor to a low nanomolar compound as a follow up to earlier work from the same group highlighting another tractable PPI target

Solvent Accessible Surface Area-Based Hot-Spot Detection Methods for Protein–Protein and Protein–Nucleic Acid Interfaces Cristian R. Munteanu, António et al J. Chem. Inf. Model., Article ASAP , DOI: 10.1021/ci500760m, Publication Date (Web): April 17, 2015, Copyright © 2015, American Chemical Society http://pubs.acs.org/doi/abs/10.1021/ci500760m

Keeping with protein-protein interactions is another method for identifying hot-spots for protein-protein and protein-nucleic acid interactions. A couple of web based tools are provided for respectively predicting protein nucleic acid and protein-protein interactions

PockDrug: A Model for Predicting Pocket Druggability That Overcomes Pocket Estimation Uncertainties Alexandre Borrel, Leslie et al Camproux J. Chem. Inf. Model., Article ASAP DOI: 10.1021/ci5006004 Publication Date (Web): April 16, 2015, Copyright © 2015, American Chemical Society,

Predicting druggability of a pocket of a protein is a tricky business as highlighted in this report outlining a new method which appears to be more accurate than existing methods. The tool PockDrug which is reported to be better able to cope with uncertainty in pocket boundaries and highlights the importance of getting the estimate of a pocket to give improved druggability prediction.

Endogenous Allosteric Modulators of G Protein–Coupled Receptors Emma T. van der Westhuizen, Celine Valant, Patrick M. Sexton, and Arthur Christopoulos J Pharmacol Exp Ther May 2015 353:246-260; published ahead of print February 3, 2015, doi:10.1124/jpet.114.221606 http://jpet.aspetjournals.org/content/353/2/246.abstract

Finally a report looking at endogenous allosteric modulators of GPCR’s a topic that perhaps doesn’t get the recognition it deserves and arguably relates to the PPI topics already discussed. After all many PPI’s are regulating the activity of other proteins via what is effectively an allosteric interaction which then begs the question how many small molecule allosteric modulators are in fact acting at PPI sites

 

More screening PAIN

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Another valuable contribution form the Monash group on PAINS 1 – frequent hitters in screening assays. This time aminothiazoles are in the spot light – those favourites of early parallel synthesis aficionados with the mix of alpha-bromomethylketone and substituted thiourea. The authors observed issues with this motif in fragment libraries and in conventional screening decks – not necessarily that they were really bad just that they did hit frequently and were challenging to attempt to optimise – best steer clear.

In another paper 2 where the authors were screening for HDAC inhibitors using a thiol trap fluorescence read-out several series of compounds were highlighted showing activity due to thiol trapping which had not been detected with their cheminformatics filters prior to running the assay.  Compounds tended to show non-specific thiol trapping, furthermore these same compounds were shown to have activity across a range for targets (Pubchem) and unfortunately had been reported as tools for other targets. This paper is sumamrised nicely by Erlanson 3 with additional commentary on PAINS compounds

  1. S. M. Devine et al J. Med. Chem., Article ASAP DOI: 10.1021/jm501402x Publication Date (Web): January 16, 2015 Copyright © 2015, American Chemical Society
  2. J. L. Dahlin, et al, J. Med. Chem., Article ASAP DOI: 10.1021/jm5019093 Publication Date (Web): February 21, 2015 Copyright © 2015, American Chemical Society
  3. D. A. Erlanson J. Med. Chem., Article ASAP, DOI: 10.1021/acs.jmedchem.5b00294, Publication Date (Web): February 24, 2015 Copyright © 2015, American Chemical Society

A different take on kinase inhibitors and selective inhibition of substrate phosphorylation

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An article 1 that I really found fascinating and potentially with substantial consequences in the way we think about the “activity” of compounds and the way we set up biological screens is the work from AZ discussing selective inhibitors of kinase substrate activation. Specifically the AZ team have identified ATP competitive inhibitors of p38 kinase, which as with many kinases has multiple substrates, that selectivity inhibit the phosphorylation of one substrate over another. Compounds from two chemical series were identified and the authors showed that the substrate selectivity was due to a specific polar interaction. The key to identifying these compounds was the use of the endogenous target and off-target substrates in the primary screen rather than an artificial substrate that virtually everyone else in the field has been using.  I am not aware of this approach being used previously but will be happy to be proved wrong.

  1. J. G. Cumming et al J. Med. Chem., 2015, 58 (1), 278–293

Aryl halides

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A couple of papers looking at different aspects of halogens in drug discovery. Firstly 1 the frequency of para-substituted chlorophenyl compounds both in commercial reagents and in marketed drugs is disproportionately high relative to ortho- or meta- substitution. The authors speculate that the high frequency of para-chlorophenyl in drugs may reflect both reagent availability and the use of Topliss decision tree strategies for substituent selection. Interestingly meta-substitution is quite rare while ortho is comparatively ore common at about 25% the frequency of a para-chlorosubstituent certainly conformational effects will be playing a big role in this. Of course introducing an ortho-substituent is often the reaction that fails in array chemistry requiring bespoke synthesis.

Halogen bonding is getting an increasing profile thus scoring functions to recognise opportunities for halogen bonding are valuable 2. Perhaps an ortho chloro substituent has greater difficulty in achieving a good alignment for a robust interaction although that doesn’t explain the infrequent occurrence of meta-substituted arylchlorides.

  1. Understanding Our Love Affair with p-Chlorophenyl: Present Day Implications from Historical Biases of Reagent Selection Dean G. Brown, Moriah M. Gagnon and Jonas Boström J. Med. Chem., Article ASAP DOI: 10.1021/jm501894t Publication Date (Web): February 19, 2015 Copyright © 2015, American Chemical Society http://pubs.acs.org/doi/abs/10.1021/jm501894t
  2. Evaluating the Potential of Halogen Bonding in Molecular Design: Automated Scaffold Decoration Using the New Scoring Function XBScore Markus O. Zimmermann, Andreas Lange and Frank M. Boeckler J. Chem. Inf. Model., Article ASAP DOI: 10.1021/ci5007118 Publication Date (Web): February 19, 2015 Copyright © 2015, American Chemical Society, http://pubs.acs.org/doi/abs/10.1021/ci5007118