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

Publication date: Available online 19 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ian S. Cloudsdale, John K. Dickson, Thomas E. Barta, Brian S. Grella, Emilie D. Smith, John L. Kulp, Frank Guarnieri, John L. Kulp
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 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 mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC50s < 100 nM) with good oral bioavailability (F >20-58%).

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