In silico studies of piperazine derivatives as potent anti-proliferative agents against PC-3 prostate cancer cell lines

Quantitative Structure Activity Relationship studies were carried out on arylpiperazine derivatives to investigate their anti-proliferate activity against prostate PC-3 cancer cell lines. The built model with statistical parameters; R(2) = 0.8483, R(2)(adj) = 0.8078, Q(2)(cv) = 0.7122 and external validation (R(2)(test)) 0.6682 revealed that the anti-proliferate activities were strongly dependent on the descriptors: MATS7c, MATS3e, maxwHBa and WPSA-3. The Variance Inflation Factor of the descriptors were all greater than one but less than two and all descriptors were poorly correlated (r < 0.4). A graph of the experimental activities and predicted activities showed a high correlation and a William's plot showed the presence of only one outlier compound. These results are similar to those reported for stable and robust models with high predicting power. Molecular docking studies of compounds 5 (1-phenyl-4-(4-(2-(p-tolyloxy)ethyl)benzyl)piperazine) and 17 (4-(4-((4-phenylpiperazin-1-yl)methyl)phenethoxy)benzonitrile) with the androgen receptor gave binding affinities of −7.5 and −7.1 kcal/mol respectively. Compound 5 formed a more stable complex having hydrogen, electrostatic and hydrophobic bond interactions while compound 17 had hydrogen and hydrophobic bond interactions only. This study provides a roadmap to the design of more potent anti-prostate cancer compounds.