Al-Harbi Alhanouf I, Ullah Asad, Almanaa Taghreed N, Gul Farah, Khan Saifullah, Waheed Yasir, Ul Haq Mahboob, Muhammad Riaz, Khurram Muhammad, Ullah Ameen, Ahmad Sajjad
Department of Medical Laboratory, College of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia.
Department of Health and Biological Sciences, Abasyn University, Peshawar, Pakistan.
J Biomol Struct Dyn. 2023 Aug 7:1-10. doi: 10.1080/07391102.2023.2245470.
The conventional course of drug discovery is a lengthy, expensive and complex process and often experiences a high failure rate. This based study screened novel drug molecules against disulfide-bond protein A1 (PaDsbA1; PDB ID of 4ZL7) using a variety of chemoinformatic and biophysics approaches. The structure-based virtual screening identified three antipseudomonal compounds (BDC_30129064, BDC_20699588 and BDC_25329008) that targeted PaDsbA1 enzyme with a binding energy score of -7.8 kcal/mol, -7.7 kcal/mol and -7.7 kcal/mol, respectively. The compounds revealed deep binding at the enzyme active pocket with close distance hydrogen bond interactions with Thr46, Pro55, Val58, Arg62, His88, and Asp180. The co-crystalized hexaethylene glycol revealed a binding energy of -6.02 kcal/mol. The docked compounds were further subjected to molecular dynamics simulation analysis in order to check the dynamic movements of docked complexes. The complexes reported no drastic changes during simulation time. In the simulation, stable compounds binding and docked conformation were accomplished. The docking and simulation results were validated using free binding energies calculation through molecular mechanics with generalized born surface area solvation and molecular mechanics Poisson Boltzmann surface area (MMGBSA/MMPBSA) approaches. The net binding energy estimated by MMGBSA for BDC_30129064, BDC_20699588 and BDC_25329008 was -75.07 kcal/mol, -77.87 kcal/mol and -59.1 kcal/mol, respectively while that of MMPBSA for the compounds was -72.47 kcal/mol, -78.99 kcal/mol and -60.991 kcal/mol, respectively. The physiochemical properties of the selected compounds indicated them to be physiochemically stable with good absorption, distribution, metabolism and elimination properties. From the above observations and predictions, the compounds can be recommended for further experimental validation in order to decipher their anti-virulence capacity in blocking disulfide bond formation in .Communicated by Ramaswamy H. Sarma.
传统的药物研发过程漫长、昂贵且复杂，而且失败率往往很高。本基础研究使用多种化学信息学和生物物理学方法，针对二硫键蛋白A1（PaDsbA1；PDB ID为4ZL7）筛选新型药物分子。基于结构的虚拟筛选确定了三种抗假单胞菌化合物（BDC_30129064、BDC_20699588和BDC_25329008），它们靶向PaDsbA1酶，结合能得分分别为-7.8千卡/摩尔、-7.7千卡/摩尔和-7.7千卡/摩尔。这些化合物在酶活性口袋处有深度结合，与Thr46、Pro55、Val58、Arg62、His88和Asp180有近距离氢键相互作用。共结晶的六甘醇的结合能为-6.02千卡/摩尔。对接的化合物进一步进行分子动力学模拟分析，以检查对接复合物的动态运动。复合物在模拟期间未报告剧烈变化。在模拟中，实现了稳定的化合物结合和对接构象。通过使用广义Born表面面积溶剂化的分子力学和分子力学泊松玻尔兹曼表面面积（MMGBSA/MMPBSA）方法计算自由结合能，对对接和模拟结果进行了验证。MMGBSA估计BDC_30129064、BDC_20699588和BDC_25329008的净结合能分别为-75.07千卡/摩尔、-77.87千卡/摩尔和-59.1千卡/摩尔，而MMPBSA对这些化合物的净结合能分别为-72.47千卡/摩尔、-78.99千卡/摩尔和-60.991千卡/摩尔。所选化合物的物理化学性质表明它们在物理化学上是稳定的，具有良好的吸收、分布、代谢和排泄特性。根据上述观察和预测，可推荐这些化合物进行进一步的实验验证，以阐明它们在阻断……中二硫键形成方面的抗毒力能力。由Ramaswamy H. Sarma传达。
