Discovering Active Chemotherapeutic Agents for Sexually Transmitted Diseases to Inhibit Pathogenic HPV-16-E6 Protein.

Vemula Vani, Manikandan Alagumuthu, Sanjay Prasad, Nikita Paul, Nithya Gajendra, Pooja Narayanaswamy, Pooja Venkataraman
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Abstract

Background: One of the most prevalent sexually transmitted diseases (STDs) is infection with the human papillomavirus (HPV). The current treatment methods comprise employing chemotherapeutic medications or doing surgery to remove the developed tumors. A more affordable option for treating HPV-related diseases has emerged with the advent of medication-based therapy. The interaction between E6 protein and E6AP generates a p53 degradation complex in HPV-infected cells, which facilitates carcinogenesis.

Objective: The purpose of this work is to use a virtual screening technique to find possible small molecule inhibitors against the HPV16 E6 protein.

Methods: Compounds 5, 7, and 10 are three new HPV 16 E6 inhibitors that were created utilizing a fragment-based methodology. The trials subset in the ZINC database was screened virtually using the structural information of these three novel chemicals, yielding 9800 hits. Using the GLIDE module of the Schrodinger software, three virtual screening phases were applied to the molecules that were collected from the database. MD simulations and DFT (Density Function Theory) were also carried out.

Results: The findings indicated that when compared to the reference molecule, luteolin, the five-hit compounds (ZINC000034853956, ZINC000001534965, ZINC000095617673, ZINC000005764481, and ZINC000071606215) demonstrated superior glide scores. Important interactions between these compounds and the HPV 16 E6 protein were seen. Using the QikProp tool, the pharmacokinetic characteristics of these hit compounds were examined. The findings demonstrated that the pharmacokinetic characteristics and oral absorption by humans of all five compounds were found to be satisfactory. Except for ZINC000005764481, all five hit compounds were predicted to be toxic; the remaining four displayed drug-like characteristics.

Conclusion: To create HPV 16 E6 inhibitors for the treatment of HPV-related disorders, the four hit compounds (ZINC000034853956, ZINC000001534965, ZINC000095617673, and ZINC00007160- 6215) can be employed as lead molecules.

发现抑制致病性HPV-16-E6蛋白的性传播疾病活性化疗药物。
背景:人乳头瘤病毒(HPV)感染是最普遍的性传播疾病之一。目前的治疗方法包括使用化疗药物或做手术切除已发展的肿瘤。随着以药物为基础的疗法的出现,治疗hpv相关疾病的一种更实惠的选择已经出现。E6蛋白与E6AP相互作用在hpv感染细胞中产生p53降解复合物,促进癌变。目的:利用虚拟筛选技术寻找抗hpv16e6蛋白的可能小分子抑制剂。方法:化合物5、7和10是利用基于片段的方法创建的三种新的HPV 16 E6抑制剂。锌数据库中的试验子集使用这三种新化学物质的结构信息进行虚拟筛选,产生9800个命中。利用薛定谔软件的GLIDE模块,对从数据库中收集的分子进行了三个虚拟筛选阶段。MD仿真和DFT(密度函数理论)也进行了。结果:与参比分子木犀草素相比,5个化合物(ZINC000034853956、ZINC000001534965、ZINC000095617673、ZINC000005764481和ZINC000071606215)表现出更高的滑动分数。这些化合物与HPV 16e6蛋白之间存在重要的相互作用。使用QikProp工具,检测这些击中化合物的药代动力学特征。结果表明,这五种化合物的药代动力学特性和人体口服吸收均令人满意。除ZINC000005764481外,其余5种命中化合物均为毒性;其余四种表现出类似药物的特征。结论:利用ZINC000034853956、ZINC000001534965、ZINC000095617673和ZINC00007160- 6215这四种成功化合物作为先导分子,可以制备用于治疗HPV相关疾病的HPV 16 E6抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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