Several publications have emerged in literature evaluating multiple docking methodologies; however to our knowledge there is no systematic evaluation of multiple free energy perturbation (FEP) methods.  Our objective was to evaluate different FEP methods that are available to us, (namely, Desmond, MCPRO+ implementation in Schrodinger and MCPRO implementation in BOSS) in a drug discovery relevant setting.  Desmond FEP is molecular dynamics based method and MCPRO implementations are based on Monte Carlo methods.  We have carefully chosen several alchemy transformation dataset with small heavy atom changes (<2).  These transformations consists of atom, ring, chain, chiral and insertion modifications.  Experimentally determined ??G variations for these modifications vary between -4 to +4 log units, i.e., 1-1000 folds in potency.  FEP calculations were performed on these chemical modifications and the results are analyzed.  This talk will address the following questions; (i) Can FEP calculation quantitatively and/or qualitatively predict the potency trend? (ii) Whether ligand and protein starting conformations have any effect on the results? (iii) Do forward and reverse reactions in FEP provide equal (magnitude) and opposite (sign) results? And, (iv) for changes involving more than 2 atoms, does stepwise transformations provide a good ??G estimate?

Evaluation of free energy perturbation methods in drug discovery: Lessons learned and recommendations

247th National Meeting (2014)

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