Water Networks In Drug Design

Leah Frye
2015 Zenodo  
Water plays a key role in the binding of small molecules to proteins and thus, for drug design, it is critical to have a clear understanding of active site water networks. Molecular dynamics simulations coupled with clustering and statistical thermodynamics allow for the prediction of the enthalpy, entropy and free energy of binding site waters. The energetics of these waters provide information on the druggability of the site and the locations of 'hot spots' which can be targeted in virtual
more » ... geted in virtual screening and lead optimization. Using the enthalpic and entropic terms, it is possible to determine which waters should be displaced with a hydrophobic group, replaced with a water mimetic, or avoided to improve potency providing a 3D roadmap for the design of ligands with improved potency and selectivity. Once compounds have been designed, free energy perturbation methods can be used to prioritize compounds for synthesis. This talk will provide examples, both retrospective and prospective, of the successful use of binding site water energetics to evaluate druggability, identify 'hot spots', assess opportunities for use of bridging waters, and facilitate the design of compounds with improved potency and selectivity. The discussion will include details on the use of these approaches in a program involving identification of lead compounds viavirtual screening followed by rapid optimization to a development candidate that has progressed into clinical trials.
doi:10.5281/zenodo.32668 fatcat:7isl2fkopvbzzichcol5cw3axq