Exploration of Angiotensin II Type 1 Receptor Modulators by Molecular Fingerprints and Docking Simulations

Abstract

Background: Overexpression of Angiotensin Type 1 (AT1) receptor along with other deregulated oncogenic factors, for e.g. Vascular Endothelial Growth Factor (VEGF) triggers angiogenesis, which is one of the hallmarks of cancer. AT1 receptor, being a key component of the renin - angiotensin system (RAS), also helps in the regulation of blood pressure. In the present study, we report on the identification of novel Angiotensin II Type 1 receptor modulators from among the 265,242 molecules deposited in the NCI compound database (Release 4, 2012) by several rounds of In silico screening steps. Methods: The screening steps involved Lipinski's filter to eliminate the non-drug like candidates followed by fingerprint based similarity filtering using 950 known reference set of AT1 receptor binders. Further screening exercises such as, iterative GOLD based docking and binding free energy calculations were performed to arrive at potential AT1 receptor binding hit candidates. The 2D structural and bioactivity data of the known AT1 receptor modulators retrieved from BindingDB database were also critically reviewed. Results: Docking based virtual screening followed by high flexible docking resulted 10 best fit candidates, which had binding modes roughly similar to the cocrystallized ligand, ZD7155. Of the ten shortlisted candidates, NSC407757 had the binding affinity, on-par, as of the known reference ligand, ZD7155 towards AT1 receptor. An interesting observation of this study is that, the high binding affinity of the hit candidates may be attributed to the similar binding orientation and interactions as of the reference molecule independent of structural similarity with the known AT1 receptor modulators. Conclusion: The hit candidates reported in the present study hold promise as the potential new AT1 receptor modulators. Further study involving structural optimization, synthesis and In vitro binding experiments is warranted for the accelerated discovery of high efficacy novel AT1 receptor modulators.