E-pharmacophore based virtual screening for identification of dual specific PDE5A and PDE3A inhibitors as potential leads against cardiovascular diseases

Abstract The need of circumventing life-threatening cardiovascular disorders (CVDs) and pulmonary hypertension (PHT) worldwide prompts researchers to develop effective therapeutic agents. Crucial role of cyclic nucleotide phosphodiesterase-5 (PDE5A) and cyclic nucleotide phosphodiesterase-3 (PDE3A) in cardiovascular signaling makes them potential drug targets for the treatment of CVDs and PHT. In this study, one-drug-multiple-target strategy has been employed to screen inhibitors exhibiting dual specificity through Phase-generated and statistically validated e-pharmacophore models of PDE5A and PDE3A. An extensive CoCoCo database of 7 million compounds with ∼150,000,000 conformations was virtually screened by sequential e-pharmacophore mapping followed by Lipinski Rule of Five (RO5) evaluation and hierarchical docking simulations. Finally, docked hits were subjected to rigorous MMGBSA analysis to estimate the relative spatial affinity of the drug-like compounds. The hits (354 and 366 ligands against PDE5A and PDE3A, respectively) were further optimized through 2D clustering followed by a comprehensive 2D and 3D interaction analysis. Five structurally diverse hits mapped equally well with the e-pharmacophore models and showed promising inhibitory interactions with conserved four catalytic features of PDE5A and PDE3A, thus exhibiting dual specificity. Proposed lead compounds exhibited the lowest MMGBSA binding energies and were found to be in agreement with Lipinski Rule of Five (RO5) and ADME/Tox criteria as compared to sildenafil. The proposed dual inhibitors could thus provide promising outcomes for the discovery of dual as well as multipotent drug like compounds after lead optimization and primary therapeutic interventions. Graphical Abstract Communicated by Ramaswamy H. Sarma

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