E-pharmacophore filtering and molecular dynamics simulation studies in the discovery of potent drug-like molecules...

Chronic kidney disease (CKD) is a prominent health issue reported globally. The level of the vitamin D receptor (VDR) and cytochrome P450 enzyme 24-hydroxylase (CYP24A1) are crucial in the pathogenesis of secondary hyperparathyroidism (sHPT) in CKD. An elevated expression of the CYP24A1 leads to the deficiency of vitamin D and resistance to vitamin D therapy. Hence, VDR agonists and CYP24A1 antagonists are suggested to CKD patients for the management of biochemical complications. CTA-018 is a recently reported analog and acts as a potent CYP24A1 inhibitor. It inhibits CYP24A1 with an IC₅₀ 27 ± 6 nM, about 10 times more potentially than the non-selective inhibitor ketoconazole (253 ± 20 nM), and it is also been reported to induce the VDR expression. Thus, CTA-018 is under clinical trial among CKD patients. In this study, combined molecular docking and pharmacophore filtering were employed to identify compounds better than CTA-018. A huge set of 9127 compounds from Sweet Lead database were docked into the active site of VDR using Glide XP program. E-pharmacophore was developed from both the targets along with CTA-018. The compounds retrieved from the two different pharmacophore-based screening were re-docked into the active site of CYP24A1. The hits that bind well at both the active sites and matched with the pharmacophore models were considered as possible dual functional molecules against VDR and CYP24A1. Further, molecular dynamics simulation and subsequent energy decomposition analyses were also performed to study the role of specific amino acids in the active site of both VDR and CYP24A1.