HYLSOVÁ, Michaela, Benoit, Jean-Pierre CARBAIN, Jindřich FANFRLIK, Lenka MUSILOVÁ, Susanta HALDAR, Cemal KOPRULUOGLU, Haresh AJANI, Pathik BRAHMKSHATRIYA, Radek JORDA, Vladimír KRYŠTOF, Pavel HOBZA, Aude ECHALIER, Kamil PARUCH and Martin LEPŠÍK. Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines. European Journal of Medicinal Chemistry. PARIS: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, vol. 126, January, p. 1118-1128. ISSN 0223-5234. doi:10.1016/j.ejmech.2016.12.023. 2017.
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Basic information
Original name Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines
Authors HYLSOVÁ, Michaela (203 Czech Republic, belonging to the institution), Benoit, Jean-Pierre CARBAIN (250 France, belonging to the institution), Jindřich FANFRLIK (203 Czech Republic), Lenka MUSILOVÁ (203 Czech Republic, belonging to the institution), Susanta HALDAR (356 India), Cemal KOPRULUOGLU (792 Turkey), Haresh AJANI (356 India), Pathik BRAHMKSHATRIYA (356 India), Radek JORDA (203 Czech Republic), Vladimír KRYŠTOF (203 Czech Republic), Pavel HOBZA (203 Czech Republic), Aude ECHALIER (250 France), Kamil PARUCH (203 Czech Republic, guarantor, belonging to the institution) and Martin LEPŠÍK (203 Czech Republic).
Edition European Journal of Medicinal Chemistry, PARIS, ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2017, 0223-5234.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30104 Pharmacology and pharmacy
Country of publisher France
Confidentiality degree is not subject to a state or trade secret
Impact factor Impact factor: 4.816
RIV identification code RIV/00216224:14310/17:00096547
Organization unit Faculty of Science
Doi http://dx.doi.org/10.1016/j.ejmech.2016.12.023
UT WoS 000396804600086
Keywords in English Cyclin-dependent kinase 2; ATP-competitive type I inhibitors; Pyrazolopyrimidine; Quantum mechanical scoring; Protein-ligand binding; Molecular dynamics; Water thermodynamics; X-ray crystal structure
Tags AKR, NZ, rivok
Changed by Changed by: Ing. Nicole Zrilić, učo 240776. Changed: 3/4/2018 15:31.
Abstract
We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R-2 = 0.49). However, the addition of the active-site waters resulted in significant improvement (R-2 = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors. (C) 2016 Elsevier Masson SAS. All rights reserved.
Links
EE2.3.30.0037, research and development projectName: Zaměstnáním nejlepších mladých vědců k rozvoji mezinárodní spolupráce
LM2015063, research and development projectName: Národní infrastruktura chemické biologie (Acronym: CZ-­OPENSCREEN)
Investor: Ministry of Education, Youth and Sports of the CR
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