Structure-Based Rational Design and Virtual Screening of Valsartan Drug Analogs towards Developing Novel Inhibitors of Angiotensin II Type 1 Receptor

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Antihypertensive sartans, such as valsartan (VST), have been proven to competitively block access to angiotensin II type 1 receptor (AT1R), regulating arterial blood pressure. Despite various commercially available sartan drugs, more effective novel inhibitors capable of appropriate blood pressure control are still required. Here we suggest the rational design of new valsartan analogs based on the structural modification of the parent VST drug molecule. Six transformation routes of a VST scaffold were considered. The first three schemes are based on functionalizing the VST carboxylic group either into an ester group or an amide moiety, following different degrees of further chemical modifications. Next, the role of tetrazole ring alkylation in tuning inhibitory activity is examined. Finally, two series of deep recursive structural alterations of a parent VST drug were also outlined utilizing Ugi and Passerini reactions. The inhibitory activity of all novel VST derivatives against AT1 receptor was screened using molecular docking calculations, followed by ADMET property analysis. Moreover, the binding affinity of ten well-known commercial sartans was also subject to re-docking against AT1R, allowing direct comparison with our designed VST derivatives. Altogether, our findings suggest that some proposed VST analogs may be promising candidates for developing and synthesizing novel antihypertensive agents.