Role of deleterious nsSNPs of klotho protein and their drug response: a computational mechanical insights

Abstract

Worldwide, the burden of chronic kidney disease (CKD) has increased rapidly and is a lethal disease. The klotho protein plays a vital role in the regulatory mechanism in the progression of CKD. Particularly the decreased expression of klothoand its genetic variations might affect the potency of drugs. This study aims to identify a new drug molecule, which works equipotential in all types of klotholike wild and mutant variants. All non-synonymous SNPs were predicted by several SNP tools. Where, two missense variants were examined as vulnerable, significantly damaging, and also involved in the structural conformational changes of the protein. Based on structure-based screening, E-pharmacophore screening, binding mode analysis, binding free energy analysis, QM/MM, and molecular dynamics analysis a lead compound (Lifechemical_F2493-2038) was identified as an effective agonistic molecule hence the identified Lifechemical_F2493-2038 compound is well bound to the wild and mutant proteins which found to increase the expression of klotho. Communicated by Ramaswamy H. Sarma