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Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations.

Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations.
Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations.
The rational development of specific inhibitors for the ~500 protein kinases encoded in the human genome is impeded by poor understanding of the structural basis for the activity and selectivity of small molecules that compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects –so far undetected by crystallography– affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP-binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK-inhibitor interactions, and explain the unexpectedly high potency of certain inhibitors like 3-(3H-Imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures, and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors
0022-2623
5141-5153
Heady, Lucy
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Fernandez-Serra, Marivi
d93a875b-6645-4a0e-afac-db4f7780ad18
Mancera, Ricardo L.
b547717c-f91b-42a2-9f73-a096d1b47bd9
Joyce, Sian
0b3a077b-add9-44b1-aed1-ac85a5cf8154
Venkitaraman, Ashok R.
fe199119-1c25-4f0e-8275-0e07305c5384
Artacho, Emilio
c1c426ee-4b9e-4d86-9e19-08c4e584909c
Skylaris, Chris-Kriton
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Colombi Ciacchi, Lucio
9077c6a6-072c-4002-aeda-067856f7baa4
Payne, Mike C.
abb730ea-f683-4bec-a7e0-766f0a180a05
Heady, Lucy
2f3d848e-5c8d-4038-bfd2-b1ffe7e10e44
Fernandez-Serra, Marivi
d93a875b-6645-4a0e-afac-db4f7780ad18
Mancera, Ricardo L.
b547717c-f91b-42a2-9f73-a096d1b47bd9
Joyce, Sian
0b3a077b-add9-44b1-aed1-ac85a5cf8154
Venkitaraman, Ashok R.
fe199119-1c25-4f0e-8275-0e07305c5384
Artacho, Emilio
c1c426ee-4b9e-4d86-9e19-08c4e584909c
Skylaris, Chris-Kriton
8f593d13-3ace-4558-ba08-04e48211af61
Colombi Ciacchi, Lucio
9077c6a6-072c-4002-aeda-067856f7baa4
Payne, Mike C.
abb730ea-f683-4bec-a7e0-766f0a180a05

Heady, Lucy, Fernandez-Serra, Marivi, Mancera, Ricardo L., Joyce, Sian, Venkitaraman, Ashok R., Artacho, Emilio, Skylaris, Chris-Kriton, Colombi Ciacchi, Lucio and Payne, Mike C. (2006) Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations. Journal of Medicinal Chemistry, 49 (17), 5141-5153. (doi:10.1021/jm060190+).

Record type: Article

Abstract

The rational development of specific inhibitors for the ~500 protein kinases encoded in the human genome is impeded by poor understanding of the structural basis for the activity and selectivity of small molecules that compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects –so far undetected by crystallography– affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP-binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK-inhibitor interactions, and explain the unexpectedly high potency of certain inhibitors like 3-(3H-Imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures, and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors

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Submitted date: 17 February 2006
Published date: 3 August 2006

Identifiers

Local EPrints ID: 39164
URI: http://eprints.soton.ac.uk/id/eprint/39164
ISSN: 0022-2623
PURE UUID: dfd9496f-cc8f-4e4d-821c-eb2396b2414a
ORCID for Chris-Kriton Skylaris: ORCID iD orcid.org/0000-0003-0258-3433

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Date deposited: 21 Jun 2006
Last modified: 29 Oct 2019 01:48

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Contributors

Author: Lucy Heady
Author: Marivi Fernandez-Serra
Author: Ricardo L. Mancera
Author: Sian Joyce
Author: Ashok R. Venkitaraman
Author: Emilio Artacho
Author: Lucio Colombi Ciacchi
Author: Mike C. Payne

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