PPIs, protein pocket predictions and some endogenous allosteric modulators

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