Detailed Information on Publication Record

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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TY  - JOUR
ID  - 406517
AU  - Otyepka, Michal - Kříž, Zdeněk - Koča, Jaroslav
PY  - 2002
TI  - Dynamics and binding modes of free cdk2 and its two complexes with inhibitors studied by computer simulations
JF  - Journal of Biomolecular Structure & Dynamics
VL  - 20
IS  - 2
SP  - 141
EP  - 141
PB  - ADENINE PRESS
SN  - 07391102
KW  - cyclin dependent kinase
KW  - drug design
KW  - inhibitors
KW  - molecular dynamics
KW  - roscovitine
N2  - 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.
ER  -

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.

Abstract
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.

Abstract

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.

Links
GV201/98/K041, research and development project	Name: HCILAB - Laboratoř interakcí člověka s počítačem
GV201/98/K041, research and development project	Investor: Czech Science Foundation, HCILAB - Human-Computer Interactions Laboratory