Active and allosteric site binding MM-QM studies of Methylidene tetracyclo derivative in PCSK9 protein intended to make a safe antilipidemic agent

Abstract

Interaction of low-density lipoprotein receptors with proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a vital part 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 and LDL receptors. This study aims to evaluate the interaction between Methylidene tetracyclo derivative and PCSK9 protein through conceptual studies and compare the same with the interaction of the standard atorvastatin. Also, a comparative study was performed to analyze the interaction of molecules inside the active and allosteric sites of PCSK9. The RCSB downloaded pdb file 7S5H and the above said ligands were optimized to the level of local minima energy and configured inside the active and allosteric sites. The stability of non-bonded interactions of the complexes were analyzed using Desmond MD simulation studies. The results of docking showed that the Methylidene tetracyclo molecule possesses a two-fold higher affinity of -10.894 kcal/mol in the active site and -10.884 kcal/mol in the allosteric site. The Phe379 amino acid enabled the Methylidene tetracyclo molecule to orient inside the active site. Nine H-bonds with 6 amino acids of allosteric site increased the binding affinity compared to Atorvastatin. The MD simulation studies confirmed the stability of the nonbonded interaction of Methylidene tetracyclo molecule throughout 100 ns. This confirms that the Methylidene tetracyclo molecule will be the better hit as well as the lead molecule to modulate the behavior of PCSK9 protein.Communicated by Ramaswamy H. Sarma.