Design, synthesis and biological evaluation of renin inhibitors guided by simulated annealing of chemical potential simulations.

ABSTRACT: We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive

SUBMITTER: Cloudsdale IS 

PROVIDER: S-EPMC5553068 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature