Screening of small molecular compounds with carcinogenic inhibition function of HPV-16 E6

Cervical cancer is the second most malignant tumor among women of childbearing age, almost all cervical cancers are associated with high-risk (HR) human papillomavirus (HPV) persis-tent infection. HPV persistent infection and cell immortalization does not always cause cancer, but they increase risk and can lead to tumor formation and carcinogenesis in cooperation with other tumorigenic factors, and HR-HPV E6 oncoprotein is the mainly tumorigenic factors. E6 binds to the highly conserved sequence "LXXLL" of E6AP to form a heterodimer, which recruits and induces the degradation of tumor suppressor protein p53, trigger the immortalized transformation of infected cells, and induce its carcinogenicity. Therefore, the small molecule com-pounds, who can compete the conservative and stable binding pocket of E6-E6AP, may inhibited the carcinogenicity risk of HR-HPV E6, and HPV-16 is one of the most important HR-HPV. In this study, DOCK6, AutoDock Vina, Visual screen and GROMACS V4.5.7 were used to screen the candidate compounds from Specs library, and based on the pharmacokinetic properties and toxicity prediction by ADMSlab and ProtoX-II analytical tools, 20 E6-E6AP binding inhibi-tion small molecule compounds were selected out. They were verified by molecular interactions, cell proliferation inhibition, apoptosis induction and p53/p21 protein content/expression on SiHa (HPV-16 infected line). Ultimately, compound 4 among them with good tumor suppressive poten-tial was picked out, has the potential of medicine to HR-HPV related diseases.(c) 2023 Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).