Laboratory of Applied Thermodynamics and Molecular Modeling, Department of Chemistry, Faculty of Science, University of Tlemcen, Tlemcen, Algeria.
J Biomol Struct Dyn. 2024 Sep;42(15):7650-7666. doi: 10.1080/07391102.2023.2240906. Epub 2023 Aug 8.
Drug designing and development is an important area of research for pharmaceutical companies and chemical scientists. In this paper, we report the prediction of new ciprofloxacin derivatives by quantum chemical, molecular docking studies and pharmacokinetic properties. Theoretical studies were performed by geometry optimization computation using B3LYP level at 6-311 G (d,p) basis set. The absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters were predicted and the result show that all compounds have a great ADMET profile. To study the antibacterial, anti- activities, ciprofloxacin and its derivatives were interacted with the proteins: Thymidylate Kinase (PDB: 4QGG), Biotin carboxylase (PDB: 3JZF) and β-lactamase BlaC (PDB: 3N7W). The results of the docking studies indicate that one pharmacophore designed presents a great inhibition behavior against gram-positive organism (4QGG) and significant interactions observed between the compound and ARG48, GLN101, ARG105 and GLU37 residues of 4QGG. Also, another derivative designed present the best inhibition against gram-negative organism (3JZF) several interactions were noticed between the compound and GLY165, ILE287, LEU278, HIS236, HIS209, MET169 and LYS159 residues of (3JZF). As well as, one designed candidate is good inhibitors for β-lactamase (3N7W) multiple no bonded interactions were observed between the compound and SER84, ILE117, ASN186, LYS87, ARG187, ASN186 and THR251 residues of(3N7W). Molecular dynamics (MD) simulation study was also performed for 100 ns to confirm the stability behaviour of the main protein and inhibitor complexes. The MD simulation study validated the stability of three compounds in the protein binding pocket as potent binders. Natural bonding orbital analysis, reactivity indices and molecular electrostatic potential were carried out. The research finding of this study can be helpful to design a new potent antibacterial, antimycrobacterium candidate's drugs that will serve as the basis for future and research.Communicated by Ramaswamy H. Sarma.
药物设计与开发是制药公司和化学科学家的一个重要研究领域。在本文中，我们报告了通过量子化学、分子对接研究和药代动力学性质来预测新的环丙沙星衍生物。理论研究是通过使用 B3LYP 水平在 6-311G(d,p)基组上的几何优化计算进行的。预测了吸收、分布、代谢、排泄和毒性（ADMET）参数，结果表明所有化合物都具有良好的 ADMET 特征。为了研究抗菌、抗活性，将环丙沙星及其衍生物与蛋白质：胸苷酸激酶（PDB：4QGG）、生物素羧化酶（PDB：3JZF）和β-内酰胺酶 BlaC（PDB：3N7W）相互作用。对接研究的结果表明，设计的一个药效团对革兰氏阳性菌（4QGG）表现出很强的抑制作用，并且在化合物和 4QGG 的 ARG48、GLN101、ARG105 和 GLU37 残基之间观察到显著的相互作用。此外，设计的另一种衍生物对革兰氏阴性菌（3JZF）表现出最好的抑制作用，在化合物和 3JZF 的 GLY165、ILE287、LEU278、HIS236、HIS209、MET169 和 LYS159 残基之间观察到多个相互作用。同样，一个设计的候选物是β-内酰胺酶（3N7W）的良好抑制剂，在化合物和 SER84、ILE117、ASN186、LYS87、ARG187、ASN186 和 THR251 残基之间观察到多个非键相互作用。还进行了 100ns 的分子动力学（MD）模拟研究，以确认主要蛋白质和抑制剂复合物的稳定性行为。MD 模拟研究验证了三种化合物在蛋白质结合口袋中的稳定性，它们是有效的配体。进行了自然键轨道分析、反应性指数和分子静电势分析。这项研究的发现可以帮助设计新的有效的抗菌、抗分枝杆菌候选药物，为未来的研究提供依据。由 Ramaswamy H. Sarma 交流。
