Dynamics and binding modes of free cdk2 and its two complexes
with inhibitors studied by computer simulations

J 2002

Dynamics and binding modes of free cdk2 and its two complexes with inhibitors studied by computer simulations

OTYEPKA, Michal, Zdeněk KŘÍŽ and Jaroslav KOČA

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

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10610 Biophysics

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

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

Abstract

V originále

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

Investor: Czech Science Foundation, HCILAB - Human-Computer Interactions Laboratory

Citovat

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.

@article{406517,
   author = {Otyepka, Michal and Kříž, Zdeněk and Koča, Jaroslav},
   article_location = {GUILDERLAND},
   article_number = {2},
   keywords = {cyclin dependent kinase; drug design; inhibitors; molecular dynamics; roscovitine},
   language = {eng},
   issn = {0739-1102},
   journal = {Journal of Biomolecular Structure & Dynamics},
   title = {Dynamics and binding modes of free cdk2 and its two complexes with inhibitors studied by computer simulations},
   volume = {20},
   year = {2002}
}

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  -

OTYEPKA, Michal, Zdeněk KŘÍŽ and Jaroslav KOČA. Dynamics and binding modes of free cdk2 and its two complexes with inhibitors studied by computer simulations. \textit{Journal of Biomolecular Structure \&{} Dynamics}. GUILDERLAND: ADENINE PRESS, 2002, vol.~20, No~2, p.~141-154. ISSN~0739-1102.

Detailed Information on Publication Record