Design, identification and validation of Calcium Adenosine Triphosphatase Isoform 2a (SERCA2a) receptor modulators : a novel drug target for the treatment of heart failure

Abstract

Heart failure is a significant global health concern, with the Calcium Adenosine Triphosphatase Isoform 2a receptor emerging as a potential druggable target for enhancing contractile function in failing hearts. The aim of this study was to identify novel SERCA2a modulators using the Istaroxime agonist scaffold as a lead molecule, employing Virtual Screening and de novo drug design methods. The small molecule antagonist Cyclopiazonic Acid guided the exploration by identifying critical binding moieties and interactions in the receptor's Ligand Binding Pocket. Istaroxime was extracted from its cognate receptor and subjected to docking and Ligand Binding Pocket analysis using Sybyl-X® v1.1. Seed structures were created for de novo drug design and Virtual Screening identified potential 'hit' molecules using the Istaroxime scaffold. A comprehensive software suite was used for the completion of this project, including Sybyl-X® v1.1, ZINCPharmer, MONA®, X-Score®, LigBuilder® v1.2, and BIOVIA Discovery Studio Visualizer® v21.1. The primary goal was to discover and optimise novel SERCA2a agonist molecules with high binding affinity. Virtual Screening yielded 10 molecules with docking scores ranging from 4.78 to 5.93, with the most favourable affinities selected for in-depth analysis. The POCKET and GROW algorithms of LigBuilder® v1.2 were used to identify critical binding sites for seed generation, employing a 2D topology map as a tool. Analysis of the top three affinity structures from Virtual Screening confirmed their successful binding to the SERCA2a receptor. However, ZINC92782902 and ZINC94187178 presented challenges due to their inherent hydrophilicity which could negatively impact absorption and excretion. ZINC92121006, with a LogP of 2.36, showed potential for optimisation through strategic structural modifications to improve intestinal absorption and oral bioavailability. De novo based design revealed improved affinity in the novel generated molecules compared to the template ligand. Six distinct molecules generated from different seeds demonstrated the highest binding scores, surpassing the baseline affinity of the template molecule (7.06). Among them, the de novo molecule labelled as ‘result_024’ from Seed 5 displayed the highest pKd value of 9.97, excelling in both molecular weight and LogP aspects. These findings position ‘result_024’ as a promising candidate for further optimisation as a SERCA2a modulator.