Active and Allosteric Site Binding MOLECULAR MECHANICS-QUANTUM MECHANICS studies of STEVIOSIDE Derivative in PCSK9 Protein Intended to provide a safe Antilipidemic agent

Abstract

Interaction of low-density lipoprotein receptors with proprotein convertase subtilisin/ kexin type 9 (PCSK9) plays a vital role in causing atherosclerosis. It is the hidden precursor of clinical myocardial infarction (MI), stroke, CVD and estimates 60% of deaths worldwide. The current need is to design small molecules to prevent the interaction between PCSK9 with LDL receptors. This study aims to evaluate the PCSK9 antagonistic effect of a derivative of Stevioside ( also referred as Methylidene tetracyclo derivative) and atorvastatin. Also, a comparative study was performed to analyze the binding interaction of molecules inside the active and allosteric sites of PCSK9. The RCSB downloaded protein 7S5H and above said ligands were optimized to the local minima energy level and docked inside the active and allosteric sites. The stability of non-bonded interaction of complex was analyzed using Desmond MD simulation studies. The results of docking showed that the Methylidene tetracyclo molecule possesses a two-fold higher affinity of -10.159 kcal/mol in the active site and -10.824 kcal/mol in the allosteric site. The Phe377 amino acid made the Methylidene tetracyclo molecule orient inside the active site. Nine H-bonds with 5 amino acids of allosteric site increase the binding affinity compared to Atorvastatin. The MD simulation studies exposed that the nonbonded interaction of Methylidene tetracyclo molecule was stable throughout 100ns. This confirms the Methylidene tetracyclo molecule will be the better hit as well as the lead molecule to inhibit PCSK9 protein.