Department of Bioinformatics, Alagappa University, Karaikudi, Tamilnadu, India.
J Biomol Struct Dyn. 2024 Apr;42(6):2886-2896. doi: 10.1080/07391102.2023.2214230. Epub 2023 May 22.
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.
在全球范围内，慢性肾脏病（CKD）的负担迅速增加，是一种致命的疾病。klotho 蛋白在 CKD 进展的调节机制中起着至关重要的作用。特别是 klotho 的表达降低及其遗传变异可能会影响药物的效力。本研究旨在鉴定一种新的药物分子，该分子在所有类型的 klotho 野生型和突变型变体中都具有同等效力。通过几种 SNP 工具预测了所有非同义 SNP。其中，两个错义变体被认为是脆弱的、显著损伤的，并且还涉及到蛋白质结构构象的变化。基于结构筛选、E-药效团筛选、结合模式分析、结合自由能分析、QM/MM 和分子动力学分析，鉴定出一种先导化合物（Lifechemical_F2493-2038）作为有效的激动剂分子，因此鉴定出的 Lifechemical_F2493-2038 化合物与野生型和突变型蛋白结合良好，发现可增加 klotho 的表达。由 Ramaswamy H. Sarma 传达。
