ABSTRACT
We identified new lead candidates which showed potent dual inhibition against phosphodiesterase-1 and 5 by a ligand-based virtual screening optimized for lead evolution. This virtual screening method, consisting of classification and regression tree analysis using 168 2-center pharmacophore descriptors and 12 macroscopic descriptors, demonstrated a high predictive ability for bioactivity of new chemical compounds. The obtained lead candidates were structurally diverse, although only the structure-activity relationship data of hydroxamic acid derivatives were used to configure the prediction model for the virtual screening.
Subject(s)
Drug Evaluation, Preclinical/methods , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Ligands , Molecular Structure , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/isolation & purification , Structure-Activity RelationshipABSTRACT
HTS and the following synthesis of a series of the compounds led us to the discovery of hydroxamic acid analogs as potent dual inhibitors of phosphodiesterase (PDE)-1 and 5. These compounds have highly related structure and deviation of the structure usually resulted in reduced potency. This result can be used to design other molecules that may be utilized for the therapy of cardiovascular symptoms that relates to cGMP level.
