BACKGROUND Several human cancers, especially cervical cancer are caused by the infection of high risk strains of human papillomaviruses (HPV), notably HPV16. It is implicated that the oncoprotein E6 expressed from HPV, is inhibiting the apoptotic pathway by binding to adaptor molecule FADD (Fas-associated death domain). Inhibiting E6 interactions with FADD could provide a promising treatment for cervical cancer. There are few small molecules reported to inhibit such interactions. However, the FADD binding site information on the HPV E6 is not currently available. This binding site information may provide an opportunity to design new small molecule inhibitors to treat E6 mediated cancers. In this study we report the possible binding pocket on HPV16 E6 oncoprotein by using activity data of reported inhibitors through a stepwise molecular modeling approach. RESULTS Blind docking and removing duplicates followed by visual inspection to determine ligand-receptor interactions provided 68 possible binding sites on the E6 protein. Individual docking of all known inhibitors lead to the identification of 28 pockets having some kind of correlation with their activity data. It was also observed that several of these pockets overlapped with each other, having some amino acids in common. Amino acids Leu50 and Cys51 were identified as key E6 residues for high affinity ligand binding which are seen in most of these pockets. In most cases, ligands demonstrated a hydrogen bond interaction with Cys51. Ala61, Arg131 and Gln107 were also frequently observed showing interactions among these pockets. A few amino acids unique to each ligand were also identified representing additional interactions at the receptor site. CONCLUSIONS After determining receptor-ligand interactions between E6 oncoprotein and the six known inhibitors, the amino acids Cys51, Leu50, Arg102, Arg131, Leu67, Val62, and Gln107 were identified to have importance in E6 inhibition. It was generally observed that Leu50 and Cys51 are necessary for high binding affinity with Cys51 being essential for hydrogen bonding. This study identified a potential binding pocket for the E6 inhibitors. Identification of the ligand binding pocket helps to design novel inhibitors of HPV16 E6 oncoprotein as a promising treatment for cervical cancer.

中文翻译：

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鉴定病毒癌蛋白HPV16 E6上的潜在结合口袋：小分子药物发现的有希望的抗癌靶标。

背景技术几种人类癌症，特别是子宫颈癌是由人类乳头瘤病毒（HPV）的高风险株特别是HPV16的感染引起的。暗示从HPV表达的癌蛋白E6通过与衔接子分子FADD（Fas相关的死亡结构域）结合而抑制凋亡途径。抑制E6与FADD的相互作用可以为宫颈癌提供有希望的治疗方法。据报道，几乎没有小分子抑制这种相互作用。但是，HPV E6上的FADD绑定位点信息当前不可用。该结合位点信息可以提供设计新的小分子抑制剂来治疗E6介导的癌症的机会。在这项研究中，我们通过逐步的分子建模方法，使用报告的抑制剂的活性数据，报告了HPV16 E6癌蛋白上可能存在的结合口袋。结果盲对接和去除重复序列，然后目视检查以确定配体-受体相互作用，从而在E6蛋白上提供了68个可能的结合位点。所有已知抑制剂的单独对接导致鉴定出28个与它们的活性数据具有某种相关性的口袋。还观察到这些口袋中的几个互相重叠，具有一些共同的氨基酸。氨基酸Leu50和Cys51被确定为高亲和力配体结合的关键E6残基，在大多数这些口袋中都可以看到。在大多数情况下，配体表现出与Cys51的氢键相互作用。Ala61，还经常观察到Arg131和Gln107表现出这些口袋之间的相互作用。还鉴定了每个配体独特的一些氨基酸，它们代表受体位点的其他相互作用。结论在确定E6癌蛋白与六种已知抑制剂之间的受体-配体相互作用后，确定了Cys51，Leu50，Arg102，Arg131，Leu67，Val62和Gln107氨基酸对E6抑制具有重要作用。通常观察到Leu50和Cys51对于高结合亲和力是必需的，而Cys51对于氢键是必不可少的。这项研究确定了E6抑制剂的潜在结合口袋。配体结合口袋的鉴定有助于设计HPV16 E6癌蛋白的新型抑制剂，将其作为宫颈癌的有前途的治疗方法。还鉴定了每个配体独特的一些氨基酸，它们代表受体位点的其他相互作用。结论在确定E6癌蛋白与六种已知抑制剂之间的受体-配体相互作用后，确定了Cys51，Leu50，Arg102，Arg131，Leu67，Val62和Gln107氨基酸对E6抑制具有重要作用。通常观察到Leu50和Cys51对于高结合亲和力是必需的，而Cys51对于氢键是必不可少的。这项研究确定了E6抑制剂的潜在结合口袋。配体结合口袋的鉴定有助于设计HPV16 E6癌蛋白的新型抑制剂，将其作为宫颈癌的有前途的治疗方法。还鉴定了每个配体独特的一些氨基酸，它们代表受体位点的其他相互作用。结论在确定E6癌蛋白与六种已知抑制剂之间的受体-配体相互作用后，确定了Cys51，Leu50，Arg102，Arg131，Leu67，Val62和Gln107氨基酸对E6抑制具有重要作用。通常观察到Leu50和Cys51对于高结合亲和力是必需的，而Cys51对于氢键是必不可少的。这项研究确定了E6抑制剂的潜在结合口袋。配体结合口袋的鉴定有助于设计HPV16 E6癌蛋白的新型抑制剂，将其作为宫颈癌的有前途的治疗方法。结论在确定E6癌蛋白与六种已知抑制剂之间的受体-配体相互作用后，确定了Cys51，Leu50，Arg102，Arg131，Leu67，Val62和Gln107氨基酸对E6抑制具有重要作用。通常观察到Leu50和Cys51对于高结合亲和力是必需的，而Cys51对于氢键结合是必不可少的。这项研究确定了E6抑制剂的潜在结合口袋。配体结合口袋的鉴定有助于设计HPV16 E6癌蛋白的新型抑制剂，将其作为宫颈癌的有前途的治疗方法。结论在确定E6癌蛋白与六种已知抑制剂之间的受体-配体相互作用后，确定了Cys51，Leu50，Arg102，Arg131，Leu67，Val62和Gln107氨基酸对E6抑制具有重要作用。通常观察到Leu50和Cys51对于高结合亲和力是必需的，而Cys51对于氢键是必不可少的。这项研究确定了E6抑制剂的潜在结合口袋。配体结合口袋的鉴定有助于设计HPV16 E6癌蛋白的新型抑制剂，将其作为宫颈癌的有前途的治疗方法。通常观察到Leu50和Cys51对于高结合亲和力是必需的，而Cys51对于氢键结合是必不可少的。这项研究确定了E6抑制剂的潜在结合口袋。配体结合口袋的鉴定有助于设计HPV16 E6癌蛋白的新型抑制剂，将其作为宫颈癌的有前途的治疗方法。通常观察到Leu50和Cys51对于高结合亲和力是必需的，而Cys51对于氢键是必不可少的。这项研究确定了E6抑制剂的潜在结合口袋。配体结合口袋的鉴定有助于设计HPV16 E6癌蛋白的新型抑制剂，将其作为宫颈癌的有前途的治疗方法。