Panwar Vivek, SenGupta Sounok, Kumar Saroj, Singh Praveen P, Kumar Arun, Azizov Shavkatjon, Gupta Manoj K, Kumar Deepak
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Himachal Pradesh, Solan, 173229 India.
Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Himachal Pradesh, Solan, 173229 India.
In Silico Pharmacol. 2024 Sep 14;12(2):83. doi: 10.1007/s40203-024-00261-w. eCollection 2024.
Oxadiazoles an important heterocyclic scaffold of medicinal importance in the field of drug discovery. In the study, a library of oxadiazole based compounds was selected for screening against STAT-3 as anti-cancer target. STAT3 is a potential target of interest in cancer therapy. A total of 544 screened library of compounds was subjected to molecular docking against STAT-3 (6NJS and 6NQU). The compounds with good dock score and binding interations were further subjected to in-silico ADME analysis followed by toxicity estimation. A total of 141 hits were selected against 6NJS and 50 hits against 6NQU and further screened for kinetic properties and drug likeliness. The compounds were screened on the basis of physico-chemical properties, solubility, gastrointestinal absorption, BBB permeability, synthetic accessibility, Lipinski and other violations. Best compounds obtained after ADME analysis were further subjected for toxicity analysis. Carcinogenecity, mutagenicity, Ames and other important parameters were considered for toxicity based screening. The best leads thus obtained (compound 114 and 40) were further subjected to molecular dynamics against the respective target proteins. MD simulations were run to access the stability of C-114 and C-40 along with the dynamic behaviour of both complexes for about 100 ns and shows good stability with the proteins.
恶二唑是药物研发领域中具有重要医学意义的杂环骨架。在本研究中,选择了一个基于恶二唑的化合物库,针对作为抗癌靶点的信号转导和转录激活因子3(STAT-3)进行筛选。STAT3是癌症治疗中一个潜在的重要靶点。总共544个经过筛选的化合物库与STAT-3(6NJS和6NQU)进行分子对接。对接分数和结合相互作用良好的化合物进一步进行计算机辅助的药物代谢动力学(ADME)分析,随后进行毒性评估。针对6NJS共筛选出141个命中化合物,针对6NQU筛选出50个命中化合物,并进一步筛选其动力学性质和类药性质。根据物理化学性质、溶解度、胃肠道吸收、血脑屏障通透性、合成可及性、Lipinski规则及其他违规情况对化合物进行筛选。ADME分析后获得的最佳化合物进一步进行毒性分析。基于毒性筛选考虑了致癌性、致突变性、艾姆斯试验及其他重要参数。由此获得的最佳先导化合物(化合物114和40)进一步针对各自的靶蛋白进行分子动力学研究。进行分子动力学模拟以评估C-114和C-40的稳定性以及两种复合物约100纳秒的动态行为,结果显示它们与蛋白质具有良好的稳定性。