Ligand- And structure-based virtual screening of 16-((diiso-butylamino)methyl)-6α-hydroxyvouacapane-7β,17β-lactone, a compound with potential anti-prostate cancer activity

Abstract

Prostate cancer is one of the leading causes of disease and death on the planet. The probable bioactive pose of 16-((diisobutylamino)methyl)-6α-hydroxyvouacapane-7β,17β-lactone (N,N-DHL), a pivot compound with prostatic anti-cancer activity, was investigated via a semi-empirical method (PM3) and refined with the base set 6-31+G(d,p) calculated in the DFT method at the B3LYP level of theory. This structure was used in ligand-based virtual screening for five commercial compound bases using the software ROCS and EON that selected 2000 per base and another that resulted in 100 per base, respectively. This set was used for pharmacokinetic and toxicological predictions. The molecular overlap index at 50 % steric/electrostatic provided 68 structures that were used for a molecular docking study. The results showed that of 238,922 structures, only eight, 7 (–10.9 kcal mol-1) as the best in the series and 1 (–8.1 kcal mol-1) as less favorable, with others in this range (±2.8 kcal mol-1) with their respective binding affinity: 8 (–8.2 kcal mol-1), 5 (–8.2 kcal mol-1), 4 (–8.3 kcal mol-1), 2 (–8.5 kcal mol-1), 3 (–8.6 kcal mol-1) and 6 (–8.8 kcal mol-1) remaining in the final selection. The predictions for 21 pharmacokinetic properties were within the recommended range, similar to 95 % of the drugs available on the market, with no toxicity warning. The structures showed similarity greater than 75 % to the pivot based on binding affinity and predictions but only the structures 6 and 7 were considered more promising for their potential anti-prostate cancer activity (PC-3).