Central Research Laboratory, Institute of Medical Sciences and Sum Hospital, Siksha "O" Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India.
NCDs Division, ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India.
J Cell Biochem. 2018 Dec;119(12):9838-9852. doi: 10.1002/jcb.27304. Epub 2018 Aug 20.
Leprosy (causative, Mycobacterium leprae) continues to be the persisting public health problem with stable incidence rates, owing to the emergence of dapsone resistance that being the principal drug in the ongoing multidrug therapy. Hence, to overcome the drug resistance, structural modification through medicinal chemistry was used to design newer dapsone derivative(s) (DDs), against folic acid biosynthesis pathway. The approach included theoretical modeling, molecular docking, and molecular dynamic (MD) simulation as well as binding free energy estimation for validation of newly designed seven DDs, before synthesis. Theoretical modeling, docking, and MD simulation studies were used to understand the mode of binding and efficacy of DDs against the wild-type and mutant dihydropteroate synthases (DHPS). Principal component analysis was performed to understand the conformational dynamics of DHPS-DD complexes. Furthermore, the overall stability and negative-binding free energy of DHPS-DD complexes were deciphered using Molecular Mechanics/Poisson-Boltzmann Surface Area technique. Molecular mechanics study revealed that DD3 possesses higher binding free energy than dapsone against mutant DHPS. Energetic contribution analysis portrayed that van der Waals and electrostatic energy contributes profoundly to the overall negative free energy, whereas polar solvation energy opposes the binding. Finally, DD3 was synthesized and characterized using Fourier-transform infrared spectroscopy, UV, liquid chromatography-mass spectrometry, and proton nuclear magnetic resonance techniques. This study suggested that DD3 could be further promoted as newer antileprosy agent. The principles of medicinal chemistry and bioinformatics tools help to locate effective therapeutics to minimize resources and time in current drug development modules.
麻风病（病原体，麻风分枝杆菌）仍然是一个持续存在的公共卫生问题，其发病率保持稳定，这是由于出现了对氨苯砜耐药的情况，而氨苯砜是目前多药治疗中主要的药物。因此，为了克服耐药性，通过药物化学进行了结构修饰，以设计针对叶酸生物合成途径的新型氨苯砜衍生物（DD）。该方法包括理论建模、分子对接和分子动力学（MD）模拟以及结合自由能估计，以验证在合成之前新设计的七种 DD。理论建模、对接和 MD 模拟研究用于了解 DD 与野生型和突变型二氢叶酸合成酶（DHPS）结合的模式和功效。主成分分析用于了解 DHPS-DD 复合物的构象动力学。此外，使用分子力学/泊松-玻尔兹曼表面面积技术来破译 DHPS-DD 复合物的整体稳定性和负结合自由能。分子力学研究表明，DD3 对突变型 DHPS 的结合自由能高于氨苯砜。能量贡献分析表明，范德华力和静电力对总负自由能有很大贡献，而极性溶剂化能则阻碍了结合。最后，使用傅里叶变换红外光谱、紫外光谱、液相色谱-质谱和质子核磁共振技术合成和表征了 DD3。这项研究表明，DD3 可以进一步作为新型抗麻风药物进行推广。药物化学和生物信息学工具的原理有助于找到有效的治疗方法，以减少当前药物开发模块中的资源和时间。
