Docking-based 3D-QSAR, molecular dynamics simulation studies and virtual screening of novel ONC201 analogues targeting Mitochondrial ClpP

Abstract The human ClpP proteolytic complex is highly expressed in many types of solid and nonsolid cancers and has become a promising target for anticancer agents. In recent years, small molecules with various structures targeting ClpP have been reported. These include ONC201 and its derivatives ONC212 and the TR compounds. Here we report the binding interaction modes of a series of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones ClpP-activing compounds using molecular docking, and three-dimensional quantitative structure activity relationships (3D-QSAR). Comparative molecular field analysis (CoMFA q2 =  0.862, r2 =  0.983) and topomer comparative molecular field analysis (Topomer CoMFA q2 =  0.905, r2 =  0.979) were used to establish 3D-QSAR models, which had good verification and prediction capabilities. Based on the contour maps and the information of molecular docking, 4 novel small molecules were designed and subjected to further molecular dynamics simulations (MD). The calculation of binding free energy showed that the residues ARG-78, LEU-79, GLU-82, ILE-84, HIS-116, TYR-118, TRP-146, LEU-104, PHE-105 and SER-108 of ClpP played a key role. The hydrogen bond analysis showed that SER108, TYR118, TRP146, GLU82 form stable hydrogen bonds with ClpP agonists. The MD results indicated that compound 93 could stably bind with the ClpP and might be a promising ClpP agonist candidate. The studies verified the specific binding mode of enzyme agonists through molecular docking and molecular dynamics simulations, and provided theoretical guidance for the design of new ONC201 analogues as ClpP agonists.