Drug Target Strategies

Free energy perturbation calculations as a computational assay for structure based drug design

• VF

  Victoria Feher, PhD

  Global Head, Applications Science and Modeling Services
  Schrodinger, Inc.

For ~25 years the implementation of computational methods in drug discovery has promised to deliver new drugs to candidacy faster and at lower cost than more traditional drug discovery methods. This promise is increasingly coming to fruition as computational methods have become more robust, more widely used and high powered inexpensive GPU technology allow these calculations to be completed in a timeframe that is meaningful to structure-based drug discovery teams. Notably, recent advances in free energy perturbation algorithms, such as FEP+, allow physics-based interrogation of ligand – target interactions as a predictive computational assay. A number of examples, both retrospective and prospective from our drug discovery collaborations will be provided to illustrate the implementation and success of this method. Typical discovery and optimization processes such as selection of ligands with the best target affinities within a chemical series, selection of the best ligands for target selectivity and solubility as well as maintaining potency while moving away from an ADME liability are exemplified. For each case, a set of ~100 or more virtual ligand ideas were prioritized to less than 10 to be synthesized thereby hastening the discovery process.