Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening.
Med Res Rev, 2018/09;38(6):1874-1915.
Ojeda-Montes MJ[1], Gimeno A[1], Tomas-Hernández S[1], Cereto-Massagué A[1], Beltrán-Debón R[1], Valls C[1], Mulero M[1], Pujadas G[1, 2], Garcia-Vallvé S[1, 2]
Affiliations
PMID: 29660786DOI: 10.1002/med.21499
Impact factor: 12.388
Abstract
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 IC50 ≤ 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.
Keywords: GIP; GLP-1; gliptins; hyperglycemia treatment; incretins
MeSH terms
Amino Acid Sequence; Animals; Binding Sites; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Humans; Structure-Activity Relationship; User-Computer Interface
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