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 a Jaroslav KOČA

Základní údaje

Originální název

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

Autoři

OTYEPKA, Michal (203 Česká republika), Zdeněk KŘÍŽ (203 Česká republika) a Jaroslav KOČA (203 Česká republika, garant)

Vydání

Journal of Biomolecular Structure & Dynamics, GUILDERLAND, ADENINE PRESS, 2002, 0739-1102

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10610 Biophysics

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 1.009

Kód RIV

RIV/00216224:14310/02:00006680

Organizační jednotka

Přírodovědecká fakulta

UT WoS

000179043800001

Klíčová slova anglicky

cyclin dependent kinase; drug design; inhibitors; molecular dynamics; roscovitine

Štítky

Cyclin dependent kinase, drug design, inhibitors, molecular dynamics, roscovitine

Změněno: 4. 1. 2004 17:40, prof. RNDr. Jaroslav Koča, DrSc.

Anotace

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.

Návaznosti

GV201/98/K041, projekt VaV

Název: HCILAB - Laboratoř interakcí člověka s počítačem

Investor: Grantová agentura ČR, HCILAB - Laboratoř interakcí člověka s počítačem

Citovat

OTYEPKA, Michal, Zdeněk KŘÍŽ a 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, roč. 20, č. 2, s. 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 a 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, roč.~20, č.~2, s.~141-154. ISSN~0739-1102.

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