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Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines
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SYSNO ASEP 0475922 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines Author(s) Hylsová, M. (CZ)
Carbain, B. (CZ)
Fanfrlík, Jindřich (UOCHB-X) RID, ORCID
Musilová, L. (CZ)
Haldar, Susanta (UOCHB-X) RID
Köprülüoglu, Cemal (UOCHB-X) ORCID, RID
Ajani, Haresh (UOCHB-X) ORCID, RID
Brahmkshatriya, Pathik (UOCHB-X)
Jorda, Radek (UEB-Q) ORCID, RID
Kryštof, Vladimír (UEB-Q) RID, ORCID
Hobza, Pavel (UOCHB-X) RID, ORCID
Echalier, A. (FR)
Paruch, K. (CZ)
Lepšík, Martin (UOCHB-X) RID, ORCIDSource Title European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 126, Jan 27 (2017), s. 1118-1128Number of pages 11 s. Language eng - English Country FR - France Keywords cyclin-dependent kinase 2 ; ATP-competitive type I inhibitors ; pyrazolo[1,5-a]pyrimidine ; quantum mechanical scoring ; protein-ligand binding ; molecular dynamics Subject RIV CC - Organic Chemistry OECD category Organic chemistry R&D Projects GA15-15264S GA ČR - Czech Science Foundation (CSF) GBP208/12/G016 GA ČR - Czech Science Foundation (CSF) Institutional support UOCHB-X - RVO:61388963 ; UEB-Q - RVO:61389030 UT WOS 000396804600086 EID SCOPUS 85007391424 DOI 10.1016/j.ejmech.2016.12.023 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2018
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