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

•The structure-activity relationship and mechanism of clppagonistand receptor wasstudied by computer-aided drug design, 3D-QSAR model, molecular docking and molecular dynamics simulation.•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 MD results indicated that designed compound 93 could stably bind with the ClpP and might be a promising ClpP agonist candidate.•The calculation of binding free energy showedthat 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 playeda key role.