Singh Jagbir, Mansuri Rani, Vijay Sonam, Sahoo Ganesh Chandra, Sharma Arun, Kumar Mahesh
1Division of Protein Biochemistry and Structural Biology, National Institute of Malaria Research (ICMR), Sector 8, Dwarka, New Delhi 110 077 India.
5Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India.
BMC Chem. 2019 Mar 28;13(1):43. doi: 10.1186/s13065-019-0551-5. eCollection 2019 Dec.
The increased multidrug resistance among antimalarial drugs produces the urgency of potent anti malarial to combat resistant malaria and the malaria burden worldwide. The protein which may prevent the growth or transmission of malaria parasite may be the great target for rational drug designing. phosphoethanolamine methyltransferase (pmt) absent in human catalyzes triple methylation of ethanolamine into phosphocholine for phosphatidylcholine biosynthesis from serine decarboxylation phosphoethanolamine methyltransferase pathway for the membrane development at asexual as well as sexual stages of parasite. The requires production of membrane rapidly for growth and multiplication. Hence, the phosphoethanolamine methyltransferase of was selected as drug target for rational drug designing. Using Discovery studio 3.5 software the library of zinc compounds was screened against target and analyzed. The compounds with better druglike properties and docking affinity and binding interaction for target protein were procured for in vitro analysis against culture (IC). Compounds ZINC02103914 and ZINC12882412 were found to have good druglike properties and affinity for pmt also inhibited growth at very low µM IC concentration 3.0 µM and 2.1 µM respectively also found nontoxic in vitro against HEK-293 cells. Simulation study of best inhibitor revealed the specificity for the target protein. Hence, the compounds possessed the immense probability of being inhibitors of pmt and may be optimized as antimalarial agent for combinational therapy to overcome the multidrug resistance and may also be used as template for optimization and rational drug designing.
抗疟药物中多重耐药性的增加凸显了研发强效抗疟药物以对抗耐药疟疾和全球疟疾负担的紧迫性。可能阻止疟原虫生长或传播的蛋白质可能是合理药物设计的理想靶点。人类体内不存在的磷酸乙醇胺甲基转移酶（pmt）催化乙醇胺的三重甲基化生成磷酸胆碱，用于通过丝氨酸脱羧磷酸乙醇胺甲基转移酶途径进行磷脂酰胆碱生物合成，以支持疟原虫无性繁殖和有性繁殖阶段的膜发育。疟原虫生长和繁殖需要快速产生膜。因此，疟原虫的磷酸乙醇胺甲基转移酶被选为合理药物设计的药物靶点。使用Discovery studio 3.5软件对锌化合物库进行了针对该靶点的筛选和分析。筛选出具有更好类药性质、对接亲和力以及与靶蛋白结合相互作用的化合物，用于针对疟原虫培养物的体外分析（IC）。发现化合物ZINC02103914和ZINC12882412具有良好的类药性质和对pmt的亲和力，在非常低的μM IC浓度（分别为3.0 μM和2.1 μM）下也能抑制疟原虫生长，并且在体外对HEK - 293细胞无毒。对最佳抑制剂的模拟研究揭示了其对靶蛋白的特异性。因此，这些化合物极有可能是pmt的抑制剂，可优化为用于联合治疗以克服多重耐药性的抗疟药物，也可作为优化和合理药物设计的模板。
