DOI: 10.1002/chem.200800277. Selectivity of Neutral/Weakly Basic P1 Group Inhibitors of Thrombin and Trypsin by a Molecular Dynamics Study

Selectivity of Neutral/Weakly Basic P1 Group Inhibitors of Thrombin and Trypsin by a Molecular Dynamics Study

10.1002/chem.200800277

Crossref journal-article

Wiley

Chemistry – A European Journal (311)

Abstract

AbstractMolecular dynamics (MD) simulations followed by molecular mechanics generalized Born surface area (MM‐GBSA) analyses have been carried out to study the selectivity of two neutral and weakly basic P1 group inhibitors (177 and CDA) to thrombin and trypsin. Detailed binding free energies between these inhibitors and individual protein residues are calculated by using a per‐residue basis decomposition method. The analysis of the detailed interaction energies provides insight on the protein–inhibitor‐binding mechanism and helps to elucidate the basis for achieving selectivity through interpretation of the structural and energetic results from the simulations. The study shows that the dominant factor of selectivity for both inhibitors is van der Waals energy, which suggests better shape complementarity and packing with thrombin. Nonpolar solvation free energy and total entropy contribution are also in favor of selectivity, but the contributions are much smaller. Binding mode and structural analysis show that 177 binds to thrombin and trypsin in a similar binding mode. In contrast, the CDA binds to thrombin and trypsin in very different modes.

Bibliography

Wu, E. L., Han, K., & Zhang, J. Z. H. (2008). Selectivity of Neutral/Weakly Basic P1 Group Inhibitors of Thrombin and Trypsin by a Molecular Dynamics Study. Chemistry â A European Journal, 14(28), 8704â8714. Portico.

Authors 3

Emilia L. Wu (first)
KeLi Han (additional)
John Z. H. Zhang (additional)

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Dates

Type	When
Created	17 years ago (Aug. 4, 2008, 10:24 a.m.)
Deposited	1 year, 10 months ago (Oct. 16, 2023, 11:54 p.m.)
Indexed	2 weeks, 2 days ago (Aug. 6, 2025, 8:30 a.m.)
Issued	16 years, 11 months ago (Sept. 22, 2008)
Published	16 years, 11 months ago (Sept. 22, 2008)
Published Online	16 years, 11 months ago (Sept. 22, 2008)
Published Print	16 years, 10 months ago (Sept. 26, 2008)

Funders 0

None

BibTeX

@article{Wu_2008, title={Selectivity of Neutral/Weakly Basic P1 Group Inhibitors of Thrombin and Trypsin by a Molecular Dynamics Study}, volume={14}, ISSN={1521-3765}, url={http://dx.doi.org/10.1002/chem.200800277}, DOI={10.1002/chem.200800277}, number={28}, journal={Chemistry – A European Journal}, publisher={Wiley}, author={Wu, Emilia L. and Han, KeLi and Zhang, John Z. H.}, year={2008}, month=sep, pages={8704–8714} }

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