Author, as appears in the article.: Ojeda-Montes M, Gimeno A, Tomas-Hernández S, Cereto-Massagué A, Beltrán-Debón R, Valls C, Mulero M, Pujadas G, Garcia-Vallvé S

Department: Bioquímica i Biotecnologia

URV's Author/s: Beltrán Debón, Raúl Alejandro / Cereto Massagué, Adrián José / Garcia Vallve, Santiago / Mulero Abellán, Miguel / Pujadas Anguiano, Gerard / TOMAS HERNÁNDEZ, SARA / Valls Bautista, Cristina

Keywords: Incretins Hyperglycemia treatment Glp-1 Gliptins Gip hyperglycemia treatment glp-1 gliptins gip

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.

Thematic Areas: Pharmacology & pharmacy Pharmacology Molecular medicine Medicina i General medicine Drug discovery Ciências biológicas ii Ciências biológicas i Chemistry, medicinal

licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 01986325

Author's mail: cristina.valls@urv.cat adrianjose.cereto@urv.cat raul.beltran@urv.cat gerard.pujadas@urv.cat santi.garcia-vallve@urv.cat miquel.mulero@urv.cat adrianjose.cereto@urv.cat

Author identifier: 0000-0001-5583-5695 0000-0001-9691-1906 0000-0003-2598-8089 0000-0002-0348-7497

Record's date: 2023-02-18

Papper version: info:eu-repo/semantics/acceptedVersion

Link to the original source: https://onlinelibrary.wiley.com/doi/abs/10.1002/med.21499

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Medicinal Research Reviews. 38 (6): 1874-1915

APA: Ojeda-Montes M, Gimeno A, Tomas-Hernández S, Cereto-Massagué A, Beltrán-Debón R, Valls C, Mulero M, Pujadas G, Garcia-Vallvé S (2018). Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening. Medicinal Research Reviews, 38(6), 1874-1915. DOI: 10.1002/med.21499

Article's DOI: 10.1002/med.21499

Entity: Universitat Rovira i Virgili

Journal publication year: 2018

Publication Type: Journal Publications