Ligand- and structure-based virtual screening from 16-(N,N-diisobutylaminomethyl)-6α-hydroxyivouacapan-7β,17β-lactone compound with potential anti-prostate cancer activity

Rai Campos Silva, João Gabriel Curtolo Poiani, Ryan Silva Ramos, Josivan Silva Costa, Carlos H. T. Paula Silva, Davi do Socorro Barros Brasil, Cleydson Breno Rodrigues Santos

Abstract


Prostate cancer is one of the leading causes of disease and death on the planet. The 16-(N, N-diisobutylaminomethyl)-6α-hydroxyivouacapan-7β,17β-lactone (N,N-DHL, Pivot) compound with prostatic anti-cancer activity had probable bioactive pose via semi-empirical method (PM3) and refined with base set 6-31+G(d, p) calculated in the DFT method with theory level B3LYP. This structure was used in ligand-based virtual screening for five commercial compound bases, using 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 by 50%steric/electrostatic provided 68 structures, which were for the molecular docking study. Our results showed that of 238.922 structures, in the final selection only resulted eight: 7 (-10.9 kcal.mol-1) like best in the series and 1 (-8.1 kcal.mol-1) as less favorable. The others in this range (±2.8 Kcal.mol-1) with 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). The predictions for 21 pharmacokinetic properties, were within the recommended range, similar to 95% of the drugs available on the market and no toxicity warning. The structures showed similarity with the Pivot greater than 75%. Based on binding affinity and predictions, only the structures 7 and 6 were considered more promising for potential anti-prostate cancer activity (PC-3).

Keywords


Dihydrotestosterone, Androgen Receptor, DFT/6-31+G (d, p), Virtual Screening, Derivative of vouacapan, Drug design

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DOI: https://doi.org/10.2298/JSC180129047S

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