Repurposing of ‘old’ drugs to treat both common and rare diseases has garnered huge attention of the researchers because of the high attrition rates and extortionate cost involved in new drug discovery. Almost in 100% of cases, high-risk HPV DNA has been found to be associated with cervical cancer. The viral E6 and E7 genes are regularly maintained and expressed in cervical cancer. So, the functional inhibition of E6 can be a promising therapeutic target for HPV-associated cervical cancer. In the present study, a five feature (AADRR) e-pharmacophore model was built based on amino acid residues reported by Zanier et al. and predicted by the Sitemap module of Maestro (Schrödinger). FDA-approved drugs library was screened employing the developed model and identified hits (based on phase screen score) were further put for docking and molecular dynamics (MD) simulations studies. The top two identified hits were ZINC000001543916 (valganciclovir; anti-viral drug) and ZINC000003795098 (cytarabine; anti-cancer drug). Incidentally, our target protein E6 can be classified under the field of tumour virology. Identified five hits are either purine or pyrimidine derivatives. We have also reported compound ASK4, a valganciclovir derivative as a potential E6 inhibitor. Molecular docking studies suggest that H-bond interaction with TYR32 and CYS51 amino acid residues is important for E6 inhibition. MD simulations studies indicated that the ligands might form stable complex with the E6 protein. All the designed compounds showed acceptable ADME profile. Further purine and pyrimidine scaffold can be used to design novel E6 inhibitors.

中文翻译：

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用于鉴定和设计针对宫颈癌的潜在 E6 抑制剂的药物再利用方法：计算机研究

由于新药发现涉及的高损耗率和高昂的成本，重新利用“旧”药物来治疗常见和罕见疾病引起了研究人员的极大关注。几乎在 100% 的病例中，已发现高危 HPV DNA 与宫颈癌有关。病毒 E6 和 E7 基因在宫颈癌中定期维持和表达。因此，E6 的功能抑制可能是 HPV 相关宫颈癌的一个有希望的治疗靶点。在本研究中，基于 Zanier 等人报告的氨基酸残基建立了五特征 (AADRR) 电子药效团模型。并由 Maestro (Schrödinger) 的 Sitemap 模块预测。使用开发的模型筛选 FDA 批准的药物库，并将确定的命中（基于阶段筛选分数）进一步用于对接和分子动力学 (MD) 模拟研究。确定的前两个命中是 ZINC000001543916（缬更昔洛韦；抗病毒药物）和 ZINC000003795098（阿糖胞苷；抗癌药物）。顺便说一下，我们的目标蛋白 E6 可以归类到肿瘤病毒学领域。确定的五个命中是嘌呤或嘧啶衍生物。我们还报道了化合物 ASK4，一种缬更昔洛韦衍生物作为潜在的 E6 抑制剂。分子对接研究表明，与 TYR32 和 CYS51 氨基酸残基的 H 键相互作用对于 E6 抑制很重要。MD 模拟研究表明配体可能与 E6 蛋白形成稳定的复合物。所有设计的化合物都显示出可接受的 ADME 曲线。进一步的嘌呤和嘧啶支架可用于设计新型 E6 抑制剂。