Kaur Kuldeep, Devi Bharti, Agrawal Vishal, Kumar Rajnish, Sandhir Rajat
Department of Biochemistry, Basic Medical Sciences Block-II, Sector-25, Panjab University, Chandigarh, 160014 India.
Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi, 221005 UP India.
J Proteins Proteom. 2022;13(4):227-245. doi: 10.1007/s42485-022-00098-x. Epub 2022 Nov 16.
Cytochrome P450 46A1 (CYP46A1) is a crucial enzyme in brain that converts cholesterol to 24 (S) hydroxy cholesterol thereby increasing its polarity to facilitate removal of excess cholesterol from the CNS. The inhibition of CYP46A1 with several synthetic molecules has been investigated extensively for treatment of Alzheimer's disease, Huntington's disease, glaucoma, and in hippocampal neurons from aged mice. However, phytochemicals have received far little attention in studies involving development of potential CYP46A1 inhibitors. Thus, in the present study phytoconstituents from Indian traditional medicinal plants; , and were virtually screened for interaction with CYP46A1 using computational tools. Out of three plants, six molecules from and three molecules from were shortlisted to study interactions with CYP46A1 based on the physio-chemical parameters. Fargesin, piperolactam A and coumaperine from showed the higher binding affinity and the values were - 10.3, - 9.5, - 9.0 kcal/moles respectively, whereas, withaferin A from had a binding affinity of - 12.9 kcal/mol. These were selected as potential modulators as they exhibited suitable interactions with active site residues; Tyr109, Leu112, Trp368, Gly369, and Ala474. The selected molecules were further subjected to molecular dynamics simulation. Further, the pharmacological properties of molecules were also predicted using ADMET calculator and the data revealed that all the selected compounds had good absorption as well as solubility characteristics. In addition, sesamin, fargesin, piperolactam A, and coumaperine had minimal or no toxic effects. Thus, the study successfully identified compounds from Indian medicinal plants that may serve as potential inhibitors of CYP46A1 or base structures to design novel CYP46A1 inhibitors, which may be effective in treating neurological conditions involving perturbed cholesterol homeostasis.
The online version contains supplementary material available at 10.1007/s42485-022-00098-x.
细胞色素P450 46A1（CYP46A1）是大脑中的一种关键酶，可将胆固醇转化为24（S）-羟基胆固醇，从而增加其极性，便于从中枢神经系统清除多余的胆固醇。人们已经广泛研究了几种合成分子对CYP46A1的抑制作用，用于治疗阿尔茨海默病、亨廷顿病、青光眼以及老年小鼠的海马神经元。然而，在涉及潜在CYP46A1抑制剂开发的研究中，植物化学物质受到的关注要少得多。因此，在本研究中，使用计算工具对印度传统药用植物中的植物成分进行了虚拟筛选，以确定它们与CYP46A1的相互作用。在这三种植物中，根据物理化学参数，从[植物名称1]中筛选出6种分子，从[植物名称2]中筛选出3种分子，用于研究它们与CYP46A1的相互作用。[植物名称1]中的法尔格辛、胡椒酰胺A和香豆素表现出较高的结合亲和力，其值分别为-10.3、-9.5、-9.0千卡/摩尔，而[植物名称2]中的沃替西汀A的结合亲和力为-12.9千卡/摩尔。由于它们与活性位点残基Tyr109、Leu112、Trp368、Gly369和Ala474表现出合适的相互作用，因此被选为潜在的调节剂。对所选分子进一步进行分子动力学模拟。此外，还使用ADMET计算器预测了这些分子的药理特性，数据显示所有所选化合物都具有良好的吸收和溶解性。此外，芝麻素、法尔格辛、胡椒酰胺A和香豆素的毒性最小或无毒性。因此，该研究成功地从印度药用植物中鉴定出了可能作为CYP46A1潜在抑制剂的化合物或设计新型CYP46A1抑制剂的基础结构，这些抑制剂可能对治疗涉及胆固醇稳态紊乱的神经系统疾病有效。
在线版本包含可在10.1007/s42485-022-00098-x获取的补充材料。
