Explicit treatment of active-site waters enhances quantum
mechanical/implicit solvent scoring: Inhibition of CDK2 by new
pyrazolo[1,5-a]pyrimidines

J 2017

Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines

HYLSOVÁ, Michaela, Benoit, Jean-Pierre CARBAIN, Jindřich FANFRLIK, Lenka MUSILOVÁ, Susanta HALDAR et. al.

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

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

France

Confidentiality degree

není předmětem státního či obchodního tajemství

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

Abstract

V originále

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 project

Name: Zaměstnáním nejlepších mladých vědců k rozvoji mezinárodní spolupráce

LM2015063, research and development project

Name: Národní infrastruktura chemické biologie (Acronym: CZ-OPENSCREEN)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

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, 2017, vol. 126, January, p. 1118-1128. ISSN 0223-5234. Available from: https://dx.doi.org/10.1016/j.ejmech.2016.12.023.

@article{1379096,
   author = {Hylsová, Michaela and Carbain, Benoit, JeanandPierre and Fanfrlik, Jindřich and Musilová, Lenka and Haldar, Susanta and Kopruluoglu, Cemal and Ajani, Haresh and Brahmkshatriya, Pathik and Jorda, Radek and Kryštof, Vladimír and Hobza, Pavel and Echalier, Aude and Paruch, Kamil and Lepšík, Martin},
   article_location = {PARIS},
   article_number = {January},
   doi = {http://dx.doi.org/10.1016/j.ejmech.2016.12.023},
   keywords = {Cyclin-dependent kinase 2; ATP-competitive type I inhibitors; Pyrazolopyrimidine; Quantum mechanical scoring; Protein-ligand binding; Molecular dynamics; Water thermodynamics; X-ray crystal structure},
   language = {eng},
   issn = {0223-5234},
   journal = {European Journal of Medicinal Chemistry},
   title = {Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines},
   volume = {126},
   year = {2017}
}

TY  - JOUR
ID  - 1379096
AU  - Hylsová, Michaela - Carbain, Benoit, Jean-Pierre - Fanfrlik, Jindřich - Musilová, Lenka - Haldar, Susanta - Kopruluoglu, Cemal - Ajani, Haresh - Brahmkshatriya, Pathik - Jorda, Radek - Kryštof, Vladimír - Hobza, Pavel - Echalier, Aude - Paruch, Kamil - Lepšík, Martin
PY  - 2017
TI  - Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines
JF  - European Journal of Medicinal Chemistry
VL  - 126
IS  - January
SP  - 1118-1128
EP  - 1118-1128
PB  - ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
SN  - 02235234
KW  - Cyclin-dependent kinase 2
KW  - ATP-competitive type I inhibitors
KW  - Pyrazolopyrimidine
KW  - Quantum mechanical scoring
KW  - Protein-ligand binding
KW  - Molecular dynamics
KW  - Water thermodynamics
KW  - X-ray crystal structure
N2  - 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.
ER  -

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. \textit{European Journal of Medicinal Chemistry}. PARIS: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2017, vol.~126, January, p.~1118-1128. ISSN~0223-5234. Available from: https://dx.doi.org/10.1016/j.ejmech.2016.12.023.

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