Pathophysiology Department, Biotechnology and Biopharmaceutical Laboratory, School of Biological Sciences, Universidad de Concepción, Victor Lamas 1290, P.O. Box 160-C, Concepción 4079386, Chile.
Inorganic Chemistry and Molecular Materials Center, Instituto de Ciencias Químicas Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, El Llano Subercaseaux 2801, San Miguel, Santiago 8900000, Chile.
Molecules. 2021 Jan 13;26(2):386. doi: 10.3390/molecules26020386.
The search for new antibacterial agents that could decrease bacterial resistance is a subject in continuous development. Gram-negative and Gram-positive bacteria possess a group of metalloproteins belonging to the MEROPS peptidase (M4) family, which is the main virulence factor of these bacteria. In this work, we used the previous results of a computational biochemistry protocol of a series of ligands designed in silico using thermolysin as a model for the search of antihypertensive agents. Here, thermolysin from Bacillus thermoproteolyticus, a metalloprotein of the M4 family, was used to determine the most promising candidate as an antibacterial agent. Our results from docking, molecular dynamics simulation, molecular mechanics Poisson-Boltzmann (MM-PBSA) method, ligand efficiency, and ADME-Tox properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity) indicate that the designed ligands were adequately oriented in the thermolysin active site. The Lig783, Lig2177, and Lig3444 compounds showed the best dynamic behavior; however, from the ADME-Tox calculated properties, Lig783 was selected as the unique antibacterial agent candidate amongst the designed ligands.
寻找能够降低细菌耐药性的新型抗菌药物是一个不断发展的课题。革兰氏阴性菌和革兰氏阳性菌都拥有一组属于 MEROPS 肽酶（M4）家族的金属蛋白酶，这是这些细菌的主要毒力因子。在这项工作中，我们使用了之前使用计算生物化学方法的一系列配体的计算结果，这些配体是使用枯草杆菌蛋白酶作为寻找抗高血压药物的模型在计算机上设计的。在这里，我们使用 M4 家族的金属蛋白酶枯草杆菌蛋白酶来确定最有希望的候选物作为抗菌剂。我们的对接、分子动力学模拟、分子力学泊松-玻尔兹曼（MM-PBSA）方法、配体效率和 ADME-Tox 性质（吸收、分布、代谢、排泄和毒性）的结果表明，设计的配体能够在枯草杆菌蛋白酶的活性部位适当定向。 Lig783、Lig2177 和 Lig3444 化合物表现出最好的动态行为；然而，从计算出的 ADME-Tox 性质来看，Lig783 被选为设计的配体中唯一的抗菌候选物。
