Assessment of iridoids and their similar structures as antineoplastic drugs by in silico approach

Iridoids commonly found in plants as secondary metabolites have been reported to possess significant biological activities such as anticancer, antioxidant, hypoglycemic, antimicrobial etc. The strong interactions of iridoids with cyclic-dependent kinase 8 (CDK8) protein could show inhibitory effects that could modulate tumour growth. From the molecular docking calculations, some iridoids interacted effectively with the target CDK8 protein (PDB ID: 5ICP) with better binding affinities of -9.1, -9.0, -9.0, -8.9 kcal/mol, than that observed for the native ligand with -8.7 kcal/mol and for the reference compound gemcitabine with -6.9 kcal/mol. The GI₅₀ values (<5 μM) obtained from graph-based signatures showed activity in breast, colon, leukaemia, and renal cancer cell lines. The IC₅₀ predictions as CDK2 inhibitors were greater than 10 µM with type I non-allosteric binding mode. The stability analysis of protein-ligand complex from 125 ns long molecular dynamics simulations showed moderately smooth trajectories and RSMD value around 5 Å for the docked ligands. The binding free energy changes up to -47.65 ± 5.97 kcal/mol from MMGBSA method and -30.33 ± 5.40 kcal/mol from MMPBSA method hinted at the spontaneous nature of the complex formation. Furthermore, geometrical evaluators like RMSF, R_g, SASA, and hydrogen bond count also corroborated with the structural stability of the complexes and the capacity of hit molecules to inhibit the target, indicating its therapeutic potential against cancer. The toxicity and drug-likeness from ADMET predictions suggested experimental verification and that the proposed candidates could be employed for further trials in the development of safer and more effective anticancer drugs.