We have analyzed small molecules in the Cambridge Structural Database (CSD) and retrieved cases that are challenging for traditional molecular mechanics force fields and conformational search algorithms. Namely, 130 structures were found containing an intramolecular sulfur-oxygen distance less than the sum of their van der Waals (vdW) radii. Through a combination of refitting force field torsional parameters, adding a specific atom pair vdW term, and attenuating the electrostatic interactions, we were able to obtain a significant improvement in the accuracy of geometry minimizations and conformational searches. With the improved force field parameters developed in this work, 84% of the cases generated a conformation with less than 0.50 � and 58% generated a conformation less than 0.25 � in RMSD from the crystal structure, which is a significant improvement over standard force fields. The improved parameters were then applied to the clinical candidate axitinib and used to generate an accurate conformation that could be repacked into the lowest-energy polymorph structure. The improved parameters can be mapped directly onto physical characteristics of the systems that are treated inadequately with traditional molecular mechanics force fields. These findings are being used to improve the next generation OPLS force field.

Close sulfur-oxygen contacts: Conformational analysis of small molecule crystals and improved force field treatment

243rd National Meeting (2012)

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