Validating CHARMM parameters and exploring charge distribution rules in structure-based drug design.

Using an extensive series of TIBO compounds that are non-nucleoside inhibitors of HIV-1 reverse transcriptase, we have systematically evaluated the quality of recently developed ligand parameters that are consistent with the CHARMM22 force field. Thermodynamic integration simulations for 44 pairs of TIBO compounds achieve a high level of success with an overall average unsigned error (AUE) in the relative binding affinities of 1.3 kcal/mol; however, the accuracy is strongly dependent on the size differential between the substituents sampled as well as the class of functional group. Low errors are observed among the alkyl, allyl, aldehyde, nitrile, trifluorinated methyl, and halide TIBO derivatives and large systematic errors among thioether derivatives. We have also investigated how different charge assignment schemes for small molecules impact the quality of computed binding affinities for a subset of this series. This study demonstrates the advantage of using model compounds to derive physically meaningful charge distributions and bond-charge increments for rapidly expanding fragment libraries for drug development applications. Specifically, in the absence of a bond-charge increment for a given pair of atom types, the strategy of adopting CHELPG charges from localized regions of model compounds provides reliable results when modeling with the CHARMM force field.