Screening of low molecular weight weak binders, �fragments�, and obtaining hits is a well understood process that can be achieved by many different assay techniques. Less well defined is how to proceed once a hit is obtained. Computational chemistry, and the application of multiple techniques, plays a vital role in understanding and ranking the many potential routes for fragment expansion design. Protein-ligand interactions are routinely investigated by docking and the results are often ranked using molecular mechanics (MM) based scoring functions. MM scoring functions have many limitations and as a consequence scoring functions do not adequately predict ligand binding affinity nor do they describe the interactions in sufficient detail as to accurately and illustratively guide medicinal chemistry. To rationalize binding at a quantum level, we demonstrate the application of the fragment molecular orbital (FMO) method as a novel computational methodology and its use in structure-based drug design to guide medicinal chemistry. As well as using FMO to prioritize fragment hits for expansion and rank docking results, it can also be used to perform virtual fragment expansion to help guide subsequent rounds of fragment-to-lead chemistry. The method can also be applied to the scoring of molecular probes, such as water, to assess the nature of unoccupied pockets within proteins in order to further guide compound design.

Fragment-to-lead using fragment molecular orbital QM calculations

243rd National Meeting (2012)

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