Unraveling the Potential of Epicatechin Gallate fromCrataegus oxyacanthain Targeting Aberrant Cardiac Ca2+ Signalling Proteins: An in-depthIn-SilicoInvestigation for Heart Failure Therapy

Abstract

AbstractThe cardiovascular sarcoplasmic reticulum (SR) calcium (Ca2+) ATPase is an imperative determinant of cardiac functionality. In addition, anomalies in Ca2+ handling protein and atypical energy metabolism are inherent in heart failure (HF). Moreover, Ca2+ overload in SR leads to mitochondrial matrix Ca2+ overload, which can trigger the generation of Reactive Oxygen Species (ROS), culminating in the triggering of the Permeability Transition Pore (PTP) and Cytochrome C release, resulting in apoptosis that leads to arrhythmias and numerous disorders. Although proteins involved in the molecular mechanism of Ca2+ dysfunction regarding mitochondrial dysfunction remains elusive, this study aims to assess the major Ca2+ handling proteins which may be involved in the Ca2+ malfunction that causes mitochondrial dysfunction and predicting the most effective drug by targeting the analyzed Ca2+ handling proteins through variousinsilicoanalyses.Thirteen proteins absorbed from interaction analysis were docked with four optimal phytochemicals fromCrataegus oxyacantha(COC) to identify the potential agonist/antagonist against those anomalies causing Ca2+ handling signaling proteins. Furthermore,The ADMET profile of tyramine, vitexin, epicatechin, and epicatechin gallate was acclimated to evaluate potential drugability utilizing QikProp by Schrodinger.Keeping this in view, critical molecular docking evaluations were performed using Glide (Maestro), autodock, and autodock vina.Based on the results of 156 dockings by Maestro, auto-dock, and auto-dock vina, PKA Cα with epicatechin gallate exhibits good interaction. Therefore, a 2000ns molecular dynamics (MD) simulation was utilized to assess the feasible phytochemical epicatechin gallate - PKA Cα complex binding stability utilizing Desmond. As a result, the molecular dynamics simulation study confirmed that epicatechin gallate from COC has high possibilities to inhibit the aberrant cardiac Ca2+ signaling proteins due to its conformational rigidity.