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Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening
Author(s) -
OjedaMontes María José,
Gimeno Aleix,
TomasHernández Sarah,
CeretoMassagué Adrià,
BeltránDebón Raúl,
Valls Cristina,
Mulero Miquel,
Pujadas Gerard,
GarciaVallvé Santiago
Publication year - 2018
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.21499
Subject(s) - protein data bank (rcsb pdb) , virtual screening , dipeptidyl peptidase 4 , selectivity , dipeptidyl peptidase , enzyme , homology modeling , computational biology , active site , chemistry , non covalent interactions , drug discovery , pharmacology , biochemistry , stereochemistry , diabetes mellitus , biology , endocrinology , type 2 diabetes , molecule , hydrogen bond , organic chemistry , catalysis
The inhibition of dipeptidyl peptidase‐IV (DPP‐IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP‐IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP‐IV and drug‐like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP‐IV noncovalent inhibition according to the binding site structure of DPP‐IV, (b) explain the most important selectivity cliffs for DPP‐IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP‐IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP‐IV inhibitors with IC 50 ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure–activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP‐IV available at the PDB.