QSAR, QSTR, and molecular docking studies of the anti-proliferative activity of phenylpiperazine derivatives against DU145 prostate cancer cell lines

• Main Authors: Fabian A. Ikwu, Gideon A. Shallangwa, Paul A. Mamza
• Format: Article
• Language: English
• Published: SpringerOpen 2020-07-01
• Series: Beni-Suef University Journal of Basic and Applied Sciences
• Subjects: Quantitative structure activity relationship; Quantitative structure toxicity relationship; Molecular docking; Prostate cancer; Computational chemistry
• Online Access: http://link.springer.com/article/10.1186/s43088-020-00054-y

Abstract Background Prostate cancer is the most common non-cutaneous cancer in males and accounts for about 4% of all cancer-related deaths in males annually. In silico methods provide faster, economical, and environmentally friendly alternatives to the traditional trial and error method of lead identification and optimization. This study, therefore, was aimed at building a robust QSAR and QSTR model to predict the anti-proliferate activity and toxicity of some phenylpiperazine compounds against the DU145 prostate cancer cell lines and normal prostate epithelial cells as well as carry out molecular docking studies between the compounds and the androgen receptor. Results Genetic Function Algorithm–Multilinear Regression approach was employed in building the QSAR and QSTR model. The QSAR model built had statistical parameters R 2 = 0.7792, R 2 adj. = 0.7240, Q 2 cv = 0.6607, and R 2 ext = 0.6049 and revealed the anti-proliferate activity to be strongly dependent on the molecular descriptors: VR3_Dzp, VE3_Dzi, Kier3, RHSA, and RDF55v. The QSTR model, on the other hand, had statistical parameters R 2 = 0.8652, R 2 adj. = 0.8315, Q 2 cv = 0.7788, and R 2 ext = 0.6344. The toxicity of the compounds was observed to be dependent on the descriptors MATS8c, MATS3s, ETA_EtaP_F, and RDF95m. The molecular descriptors in both models were poorly correlated (R < 0.4) and had variance inflation factors < 3. Molecular docking studies between the androgen receptor and compounds 25 and 32 revealed the compounds primarily formed hydrogen, halogen, and hydrophobic interactions with the receptor. Conclusion Findings from this study can be employed in in silico design of novel phenylpiperazine compounds. It can also be employed in predicting the toxicity and anti-proliferate activity of other phenylpiperazine compounds against DU145 prostate cancer cell lines.