Multi-Site λ-dynamics for simulated Structure-Activity Relationship studies

摘要: Multi-Site λ-dynamics (MSλD) is a new free energy simulation method that based on λ-dynamics. It has been developed to enable multiple substituents at sites common ligand core be modeled simultaneously and their energies assessed. The efficacy of MSλD for estimating relative hydration binding affinties demonstrated using three test systems. Model compounds representing identical benzene, dihydroxybenzene dimethoxybenzene molecules show total combined trajectory lengths ~1.5 ns are sufficient reliably achieve estimates within 0.2 kcal/mol less sensitive the number trajectories used generate these hybrid ligands contain up ten single site or five each two sites. Relative among six benzene derivatives calculated from simulations in very good agreement with those alchemical (with average unsigned differences 0.23 R(2)=0.991) experiment errors 1.8 R(2)=0.959). Estimates affinities 14 inhibitors HIV-1 reverse transcriptase obtained reasonable traditional (average 0.9 R(2)=0.402). For same level accuracy precision achieved ~20-50 times faster than thus reliable force field parameters can effectively screen tens hundreds structure-based drug design applications.