Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Mangalore, 575025, India.
Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Mangalore, 575025, India.
Comput Biol Chem. 2019 Feb;78:37-52. doi: 10.1016/j.compbiolchem.2018.11.005. Epub 2018 Nov 17.
Dihydropteroate synthase (DHPS) is an alluring target for designing novel drug candidates to prevent infections caused by pathogenic Escherichia coli strains. Diaryl Sulfone (SO) compounds are found to inhibit DHPS competitively with respect to the substrate pABA (p-aminobenzoate). The extra aromatic ring of diaryl sulfone compounds found to stabilize them in highly flexible pABA binding loops. In this present study, a statistically significant 3D-QSAR model was developed using a data set of diaryl sulfone compounds. The favourable and unfavourable contributions of substitutions in sulfone compounds were illustrated by contour plot obtained from the developed 3D-QSAR model. Molecular docking calculations were performed to investigate the putative binding mode of diaryl sulfone compounds at the catalytic pocket. DFT calculations were carried out using SCF approach, B3LYP- 6-31 G (d) basis set to compute the HOMO, LUMO energies and their respective location at pABA binding pocket. Further, the developed model was validated by FEP (Free Energy Perturbation) calculations. The calculated relative free energy of binding between the highly potent and less potent sulfone compound was found to be -3.78 kcal/ mol which is comparable to the experimental value of -5.85 kcal/mol. A 10 ns molecular dynamics simulation of inhibitor and DHPS confirmed its stability at pABA catalytic site. Outcomes of the present work provide deeper insight in designing novel drug candidates for pathogenic Escherichia coli strains.
二氢喋呤合成酶（DHPS）是设计新型药物候选物以预防致病性大肠杆菌菌株感染的诱人靶标。二芳基砜（SO）化合物被发现能够与底物 pABA（对氨基苯甲酸）竞争性抑制 DHPS。二芳基砜化合物的额外芳环被发现使其在高度灵活的 pABA 结合环中稳定。在本研究中，使用二芳基砜化合物数据集开发了一个具有统计学意义的 3D-QSAR 模型。通过从开发的 3D-QSAR 模型获得的等高线图说明了砜化合物中取代基的有利和不利贡献。进行分子对接计算以研究二芳基砜化合物在催化口袋中的可能结合模式。使用 SCF 方法、B3LYP-6-31G(d)基组进行 DFT 计算，以计算 HOMO、LUMO 能量及其在 pABA 结合口袋中的位置。此外，通过 FEP（自由能微扰）计算验证了所开发的模型。发现高活性和低活性砜化合物之间结合的相对自由能计算值为-3.78 kcal/mol，与-5.85 kcal/mol 的实验值相当。抑制剂和 DHPS 的 10 ns 分子动力学模拟证实了其在 pABA 催化位点的稳定性。本工作的结果提供了对设计针对致病性大肠杆菌菌株的新型药物候选物的更深入了解。
