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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

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 ...

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Publication status:
Published
Peer review status:
Peer reviewed
Version:
Accepted Manuscript

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Publisher copy:
10.1016/j.ejmech.2016.12.023

Authors


Hylsová, M More by this author
Carbain, B More by this author
Fanfrlík, J More by this author
Musilová, L More by this author
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Grant:
“Employment of Best Young Scientists for International Cooperation Empowerment” (CZ.1.07/2.3.00/30.0037)
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Grant:
“Employment of Best Young Scientists for International Cooperation Empowerment” (CZ.1.07/2.3.00/30.0037)
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Grant:
FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123)
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Grant:
Project “IT4Innovations National Supercomputing Center – LM2015070”
Publisher:
Elsevier Publisher's website
Journal:
European Journal of Medicinal Chemistry Journal website
Volume:
126
Pages:
1118-1128
Publication date:
2016-12-11
Acceptance date:
2016-12-09
DOI:
EISSN:
1768-3254
ISSN:
0223-5234
Pubs id:
pubs:708193
URN:
uri:43f44ab7-8d22-446e-b571-e7a93d3341d3
UUID:
uuid:43f44ab7-8d22-446e-b571-e7a93d3341d3
Local pid:
pubs:708193

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