A combined approaches of 2D-QSAR, molecular docking, molecular dynamics and ADMET prediction of anti-cancer inhibitor activity for actinonin derivatives.

Inhibition of human mitochondrial peptide deformylase (HsPDF) plays a major role in reducing growth, proliferation, and cellular cancer survival. In this work, a series of 32 actinonin derivatives for HsPDF (PDB: 3G5K) inhibitor's anticancer activity was computationally analyzed for the first time, using an study considering 2D-QSAR modeling, and molecular docking studies, and validated by molecular dynamics and ADMET properties. The results of multilinear regression (MLR) and artificial neural networks (ANN) statistical analysis reveal a good correlation between pIC50 activity and the seven (7) descriptors. The developed models were highly significant with cross-validation, the Y-randomization test and their applicability range. In addition, all considered data sets show that the AC30 compound, exhibits the best binding affinity (docking score = -212.074 kcal/mol and H-bonding energy = -15.879 kcal/mol). Furthermore, molecular dynamics simulations were performed at 500 ns, confirming the stability of the studied complexes under physiological conditions and validating the molecular docking results. Five selected actinonin derivatives (AC1, AC8, AC15, AC18 and AC30), exhibiting best docking score, were rationalized as potential leads for HsPDF inhibition, in well agreement with experimental outcomes. Furthermore, based on the study, new six molecules (AC32, AC33, AC34, AC35, AC36 and AC37) were suggested as HsPDF inhibition candidates, which would be combined with and studies to perspective validation of their anticancer activity. Indeed, the ADMET predictions indicate that these six new ligands have demonstrated a fairly good drug-likeness profile.