In silico design of low molecular weight protein-protein interaction inhibitors: Overall concept and recent advances.
Protein-protein interactions (PPIs) are carrying out diverse functions in living systems and are playing a major role in the health and disease states. Low molecular weight (LMW) "drug-like" inhibitors of PPIs would be very valuable not only to enhance our understanding over physiological processes but also for drug discovery endeavors. However, PPIs were deemed intractable by LMW chemicals during many years. But today, with the new experimental and in silico technologies that have been developed, about 50 PPIs have already been inhibited by LMW molecules. Here, we first focus on general concepts about protein-protein interactions, present a consensual view about ligandable pockets at the protein interfaces and the possibilities of using fast and cost effective structure-based virtual screening methods to identify PPI hits. We then discuss the design of compound collections dedicated to PPIs. Recent financial analyses of the field suggest that LMW PPI modulators could be gaining momentum over biologics in the coming years supporting further research in this area.
Université Paris Diderot, Sorbonne Paris Cité, UMRS 973 Inserm, Paris 75013, France; Inserm, U973, Paris 75013, France.
Mélaine A
MA
Kuenemann
Université Paris Diderot, Sorbonne Paris Cité, UMRS 973 Inserm, Paris 75013, France; Inserm, U973, Paris 75013, France; CDithem, Faculté de Pharmacie, 1 rue du Prof Laguesse, 59000 Lille, France.
Olivier
O
Sperandio
Université Paris Diderot, Sorbonne Paris Cité, UMRS 973 Inserm, Paris 75013, France; Inserm, U973, Paris 75013, France; CDithem, Faculté de Pharmacie, 1 rue du Prof Laguesse, 59000 Lille, France.
Céline M
CM
Labbé
Université Paris Diderot, Sorbonne Paris Cité, UMRS 973 Inserm, Paris 75013, France; Inserm, U973, Paris 75013, France.
David
D
Lagorce
Université Paris Diderot, Sorbonne Paris Cité, UMRS 973 Inserm, Paris 75013, France; Inserm, U973, Paris 75013, France.
Maria A
MA
Miteva
Université Paris Diderot, Sorbonne Paris Cité, UMRS 973 Inserm, Paris 75013, France; Inserm, U973, Paris 75013, France; CDithem, Faculté de Pharmacie, 1 rue du Prof Laguesse, 59000 Lille, France. Electronic address: Bruno.Villoutreix@inserm.fr.
Bruno O
BO
Villoutreix
D000818:Animals; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008970:Molecular Weight; D060066:Protein Interaction Maps / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
D008024:Ligands; D054852:Small Molecule Libraries
Bioinformatics; Chemoinformatics; Compound collection; Focused library; Protein–protein interaction inhibitors; Virtual screening