Articles producció científica> Bioquímica i Biotecnologia

Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

  • Identification data

    Identifier: imarina:5132032
    Authors:
    Ojeda-Montes M, Gimeno A, Tomas-Hernández S, Cereto-Massagué A, Beltrán-Debón R, Valls C, Mulero M, Pujadas G, Garcia-Vallvé S
    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.
  • Others:

    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 / OJEDA MONTES, Mª JOSÉ / Pujadas Anguiano, Gerard / TOMAS HERNÁNDEZ, SARA / Valls Bautista, Cristina
    Keywords: User-computer interface Structure-activity relationship Incretins Hyperglycemia treatment Humans Glp-1 Gliptins Gip Drug evaluation, preclinical Dipeptidyl-peptidase iv inhibitors Dipeptidyl peptidase 4 Binding sites Animals Amino acid sequence 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: adrianjose.cereto@urv.cat cristina.valls@urv.cat miquel.mulero@urv.cat santi.garcia-vallve@urv.cat gerard.pujadas@urv.cat raul.beltran@urv.cat
    Author identifier: 0000-0001-5583-5695 0000-0002-0348-7497 0000-0003-2598-8089 0000-0001-9691-1906
    Record's date: 2024-09-07
    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: https://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
  • Keywords:

    Chemistry, Medicinal,Drug Discovery,Molecular Medicine,Pharmacology,Pharmacology & Pharmacy
    User-computer interface
    Structure-activity relationship
    Incretins
    Hyperglycemia treatment
    Humans
    Glp-1
    Gliptins
    Gip
    Drug evaluation, preclinical
    Dipeptidyl-peptidase iv inhibitors
    Dipeptidyl peptidase 4
    Binding sites
    Animals
    Amino acid sequence
    hyperglycemia treatment
    glp-1
    gliptins
    gip
    Pharmacology & pharmacy
    Pharmacology
    Molecular medicine
    Medicina i
    General medicine
    Drug discovery
    Ciências biológicas ii
    Ciências biológicas i
    Chemistry, medicinal
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