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Binding affinities for sulfonamide inhibitors with human thrombin using Monte Carlo simulations with a linear
D K Jones-Hertzog1, W L Jorgensen
1Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
Journal of Medicinal Chemistry
|May 9, 1997
Summary
This study validates Monte Carlo simulations for calculating sulfonamide inhibitor binding to human thrombin. The method accurately predicts binding free energies (deltaGb), offering insights into enzyme-inhibitor interactions.
Area of Science:
- Biochemistry
- Computational Chemistry
- Pharmacology
Background:
- Human thrombin is a key enzyme in coagulation, making it a target for therapeutic intervention.
- Sulfonamide derivatives are investigated as potential inhibitors of human thrombin.
- Accurate prediction of binding free energy (deltaGb) is crucial for drug design.
Purpose of the Study:
- To assess the feasibility of using Monte Carlo (MC) statistical mechanics with a linear response approach to calculate deltaGb for sulfonamide inhibitors binding to human thrombin.
- To correlate calculated energy components with experimentally determined binding affinities.
- To gain insights into the molecular interactions within the thrombin active site.
Main Methods:
- Monte Carlo (MC) simulations were employed to model the binding of sulfonamide inhibitors to human thrombin.
- Calculations included Coulombic and van der Waals energy components, solvation effects, and a solvent-accessible surface area term for cavity formation.
- Results were correlated with experimentally determined free energies of binding for seven inhibitors, including MD-805 and its derivatives.
Main Results:
- The MC simulations with the linear response approach showed good correlation with experimental binding affinities, achieving an average error of 0.8 kcal/mol over a 6.0 kcal/mol range.
- The simulations provided detailed insights into the interactions within the thrombin active site.
- Specific structural features of the inhibitors, such as the orientation of the carboxylate group and methyl group, were linked to electrostatic and hydrophobic interactions, respectively.
Conclusions:
- Monte Carlo simulations are a viable method for accurately calculating the free energies of binding for sulfonamide inhibitors to human thrombin.
- The study elucidates the structural basis for binding affinity variations, highlighting the roles of electrostatic and hydrophobic interactions.
- This computational approach can guide the rational design of more effective thrombin inhibitors.