MOLECULAR MODELLING AND VIRTUAL SCREENING. APPLICATION TO THE COMPUTER-AIDED DESIGN OF ANTICANCER INHIBITORS WITH A FAVORABLE PHARMACOKINETIC PROFILE AGAINST E6 PAPILLOMAVIRUS TYPE 16

Background: Worldwide, cervical cancer (CC) is the fourth most common women cancer. It is crucial to develop more effective treatments for this disease. We aim at designing new anticancer compounds with a favorable pharmacokinetic profile, targeting the E6 oncoprotein of human papillomavirus type 16 (HPV16 E6). Methods: Computer-Aided Molecular Design (CAMD) has been carried out by the elaboration of a Quantitative Structure-Activity Relationship (QSAR) model of molecular complexation, through the correlation between the relative Gibbs free energy (rGFE) and the observed biological activities of a series of flavonoids inhibitors separated in training (TS) and validation sets (VS). Starting from the 3D crystallographic structure of the oncoprotein HPV16 E6 (Protein Data Banck (PDB) input code: 4GIZ), enzyme – inhibitor complexes were built by in situ modification of the native ligand (FLAV1, IC50exp= 850 nM), replacing substitution R-groups at nine different positions R1 – R9. Results: The complexation QSAR model equation (pIC50exp=-0.5494 × DDGcom+5.9983 (1); n=16; R2=0.98) explains 98% of the variation in biological activity by that of rGFE of the analogues used. The subsequent 3D pharmacophore model (PH4) generated from the active conformations of FLAVS (pIC50exp= 1.0177× pIC50pre – 0.0927(2); n=16; R2=0.90) was used as a virtual selection tool to identify new analogues from a virtual library (VL) reaching two digits nanomolar range predicted activity. Conclusions: The combination of molecular modelling and in silico screening of VL using the PH4 pharmacophore has led to the discovery of new promising anticancer candidates, with favorable pharmacokinetic profiles against HPV16 E6. Among them, the top two predicted respective inhibitory powers IC50 pre (50 nM and 61 nM). Peer Review History: Received 11 July 2024; Reviewed 16 September 2024; Accepted 20 October; Available online 15 November 2024 Academic Editor: Dr. Gehan Fawzy Abdel Raoof Kandeel, Pharmacognosy Department, National Research Centre, Dokki, 12622, Giza, Egypt, [email protected] Average Peer review marks at initial stage: 6.5/10 Average Peer review marks at publication stage: 8.5/10 Reviewers: Dr. Ogbonna B. Onyebuchi, Nnamdi Azikiwe University, Awka, Nigeria, [email protected] Prof. Syamsudin Abdillah, Pancasila University, Indonesia, [email protected]