Improving Force Field Parameters for Small‐Molecule Conformation Generation

Computational Pharmaceutical Solid State Chemistry, 57

Authors: D. Lupyan, Y. A. Abramov and W. Sherman

This chapter focuses on conformations of small molecules of the size of typical drug-like molecules (molecular weight <500 Da) with the aim of accurately predicting conformations, which could then be used as inputs for polymorph prediction programs. Physics-based molecular mechanics force fields are used to generate low-energy conformations, independent of the crystal packing environment, and to compare the geometries to the conformation found in the Cambridge Structural Database (CSD). The chapter specifically examines molecular interactions that are challenging for force fields (namely, close S…O and X…O interactions, where X is a halogen), and shows that more accurate conformations can often be attained with improved force field parameterization. It concludes with a description of the protocols employed in this work, and highlights a new OPLS force field, OPLS2, which shows significant advantage over other small-molecule force fields without the need for refitting.

Computational Pharmaceutical Solid State Chemistry