Ahmed Sheikh Sunzid, Rahman M Oliur, Alqahtani Ali S, Sultana Nahid, Almarfadi Omer M, Ali M Ajmal, Lee Joongku
Department of Botany, University of Dhaka, Dhaka 1000, Bangladesh.
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Toxicol Rep. 2022 Dec 14;10:56-75. doi: 10.1016/j.toxrep.2022.12.007. eCollection 2023.
In recent years, small molecule inhibition of LDHA (Lactate Dehydrogenase A) has evolved as an appealing option for anticancer therapy. LDHA catalyzes the interconversion of pyruvate and lactate in the glycolysis pathway to play a crucial role in aerobic glycolysis. Therefore, in the current investigation LDHA was targeted with bioactive phytochemicals of an ethnomedicinally important plant species (L.) Kurz. A total of 52 phytochemicals were screened against LDHA protein through molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) assay and molecular dynamics simulation to reveal three potential lead compounds such as Chrysin-7-O-glucuronide (-8.2 kcal/mol), Oroxindin (-8.1 kcal/mol) and Oroxin A (-8.0 kcal/mol). ADMET assay unveiled favorable pharmacokinetic, pharmacodynamic and toxicity properties for all the lead compounds. Molecular dynamics simulation exhibited significant conformational stability and compactness. MM/GBSA free binding energy calculations further corroborated the selection of top candidates where Oroxindin (-46.47 kcal/mol) was found to be better than Chrysin-7-O-glucuronide (-45.72 kcal/mol) and Oroxin A (-37.25 kcal/mol). Aldolase reductase and Xanthine dehydrogenase enzymes were found as potential drug targets and Esculin, the FDA approved drug was identified as structurally analogous to Oroxindin. These results could drive in establishing novel medications targeting LDHA to fight cancer.
近年来，小分子抑制乳酸脱氢酶A（LDHA）已成为一种有吸引力的抗癌治疗选择。LDHA在糖酵解途径中催化丙酮酸和乳酸的相互转化，在有氧糖酵解中起关键作用。因此，在当前的研究中，以一种具有民族药用重要性的植物物种（L.）Kurz的生物活性植物化学物质为靶点对LDHA进行研究。通过分子对接、ADMET（吸收、分布、代谢、排泄和毒性）分析以及分子动力学模拟，对总共52种植物化学物质针对LDHA蛋白进行筛选，以揭示三种潜在的先导化合物，即白杨素-7-O-葡萄糖醛酸苷（-8.2千卡/摩尔）、oroxindin（-8.1千卡/摩尔）和oroxin A（-8.0千卡/摩尔）。ADMET分析揭示了所有先导化合物具有良好的药代动力学、药效学和毒性特性。分子动力学模拟显示出显著的构象稳定性和紧凑性。MM/GBSA自由结合能计算进一步证实了对顶级候选物的选择，其中发现oroxindin（-46.47千卡/摩尔）优于白杨素-7-O-葡萄糖醛酸苷（-45.72千卡/摩尔）和oroxin A（-37.25千卡/摩尔）。发现醛糖还原酶和黄嘌呤脱氢酶为潜在的药物靶点，美国食品药品监督管理局批准的药物七叶苷被鉴定为与oroxindin结构类似。这些结果可能有助于建立针对LDHA的新型抗癌药物。
