OTYEPKA, Michal, Zdeněk KŘÍŽ and Jaroslav KOČA. Dynamics and binding modes of free cdk2 and its two complexes with inhibitors studied by computer simulations. Journal of Biomolecular Structure & Dynamics. GUILDERLAND: ADENINE PRESS, 2002, vol. 20, No 2, p. 141-154. ISSN 0739-1102.
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Basic information
Original name Dynamics and binding modes of free cdk2 and its two complexes with inhibitors studied by computer simulations
Authors OTYEPKA, Michal (203 Czech Republic), Zdeněk KŘÍŽ (203 Czech Republic) and Jaroslav KOČA (203 Czech Republic, guarantor).
Edition Journal of Biomolecular Structure & Dynamics, GUILDERLAND, ADENINE PRESS, 2002, 0739-1102.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 10610 Biophysics
Country of publisher United States of America
Confidentiality degree is not subject to a state or trade secret
Impact factor Impact factor: 1.009
RIV identification code RIV/00216224:14310/02:00006680
Organization unit Faculty of Science
UT WoS 000179043800001
Keywords in English cyclin dependent kinase; drug design; inhibitors; molecular dynamics; roscovitine
Tags Cyclin dependent kinase, drug design, inhibitors, molecular dynamics, roscovitine
Changed by Changed by: prof. RNDr. Jaroslav Koča, DrSc., učo 610. Changed: 4/1/2004 17:40.
This article presents a molecular dynamics (MD) study of the cdk2 enzyme and its two complexes with the inhibitors isopentenyladenine and roscovitine using the Cornell et at. force field from the AMBER software package. The results show that inserting an inhibitor into the enzyme active site does not considerably change enzyme structure but it seemingly changes the distribution of internal motions. The inhibitor causes differences in the domain motions in free cdk2 and in its complexes. It was found out that repulsion of roscovitine N9 substituent causes conformational change on Lys 33 side chain. Isopentenyladenine forms with Lys 33 side chain terminal amino group a hydrogen bond. It implies that the cavity, where N9 substituent of roscovitine is buried, can adopt larger substituent due to Lys 33 side chain flexibility. The composition of electrostatic and van der Waals interactions between the inhibitor and the enzyme were also calculated along both cdk2/inhibitor MD trajectories together with MM-PB/GBSA analysis. These results show that isopentenyladenine-like inhibitors could be more effective after modifications leading to an increase in their van der Waals contact with the enzyme. We suggest that a way leading to better inhibitors occupying isopentenyladenine binding mode could be: to keep N9 and N7 purine positions free, to keep 3,3-dimethylallylamino group at C6 position, and to add, e.g., benzylamino group at C2 position. The results support the idea that the isopentenyl adenine binding mode can be used for cdk2 inhibitors design and that all possibilities to improve this binding mode were not uncovered yet.
GV201/98/K041, research and development projectName: HCILAB - Laboratoř interakcí člověka s počítačem
Investor: Czech Science Foundation, HCILAB - Human-Computer Interactions Laboratory
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