Accounting for Intraligand Interactions in Flexible Ligand Docking with a PMF-Based Scoring Function

We analyzed the frequency with which intraligand contacts occurred in a set of 1300 protein–ligand complexes [Plewczynski et al. J. Comput. Chem. 2011, 32, 742–755.]. Our analysis showed that flexible ligands often form intraligand hydrophobic contacts, while intraligand hydrogen bonds are rare. The test set was also thoroughly investigated and classified. We suggest a universal method for enhancement of a scoring function based on a potential of mean force (PMF-based score) by adding a term accounting for intraligand interactions. The method was implemented via in-house developed program, utilizing an Algo_score scoring function [Ramensky et al. Proteins: Struct., Funct., Genet. 2007, 69, 349–357.] based on the Tarasov-Muryshev PMF [Muryshev et al. J. Comput.-Aided Mol. Des. 2003, 17, 597−605.]. The enhancement of the scoring function was shown to significantly improve the docking and scoring quality for flexible ligands in the test set of 1300 protein–ligand complexes [Plewczynski et al. J. Comput. Chem. 2011, 32, 742–755.]. We then investigated the correlation of the docking results with two parameters of intraligand interactions estimation. These parameters are the weight of intraligand interactions and the minimum number of bonds between the ligand atoms required to take their interaction into account