Binding Affinities for Sulfonamide Inhibitors with Human Thrombin Using Monte Carlo Simulations with a Linear Response Method

摘要: The binding of sulfonamide inhibitors to human thrombin is examined evaluate the viability calculating free energies binding, deltaGb, utilizing Monte Carlo (MC) statistical mechanics with a linear response approach. Coulombic and van der Waals energy components determined from MC simulations bound unbound solvated in water plus solvent-accessible surface area term, as an index for cavity formation, were correlated inhibitor MD-805 six derivatives. best correlations yield average error 0.8 kcal/mol seven affinities, which cover observed range 6.0 kcal/mol. also provided insights into interactions occurring active site origins variations deltaGb. Equatorial placement carboxylate group at C2 piperidine ring causes electrostatic destabilization side chain Glu-H192, while axial disposition C4-methyl reduces favorable hydrophobic P-pocket enzyme.