Binding affinities for sulfonamide inhibitors with human thrombin using Monte Carlo simulations with a linear response method

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