Cytochrome P450 1A1-mediated anticancer drug discovery: in silico findings.
BACKGROUND
Target-specific drugs may offer fewer side/adverse effects in comparison with other anticancer agents and thus save normal healthy cells to a greater extent. The selective overexpression of cytochrome P450 1A1 (CYP1A1) in tumor cells induces the metabolism of benzothiazole and aminoflavone compounds to their reactive species, which are responsible for DNA adduct formation and cell death. This review encompasses the novelty of CYP1A1 as an anticancer drug target and explores the possible in silico strategies that would be applicable in the discovery and development of future antitumor compounds.


METHODS
This review highlights the various ligand-based and target-based in silico methodologies that were efficiently used in exploration of CYP1A1 as a novel antitumor target. These methodologies include electronic structure analysis, CoMFA studies, homology modeling, molecular docking, molecular dynamics analysis, pharmacophore mapping and quantitative structure activity relationship (QSAR) studies. It also focuses on the various approaches used in the development of the lysyl amide prodrug of 5F-203 (NSC710305) and dimethanesulfonate salt of 5-aminoflavone (NSC710464) as clinical candidates from their less potent analogues.


CONCLUSIONS
Selective overexpression of CYP1A1 in cancer cells offers tumor-specific drug design to ameliorate the current adverse effects associated with existing antitumor agents. Medicinal chemistry and in vitro driven approaches, in combination with knowledge-based drug design and by using the currently available tools of in silico methodologies, would certainly make it possible to design and develop novel anticancer compounds targeting CYP1A1.
National Institute of Pharmaceutical Education and Research (NIPER), Department of Pharmacoinformatics, S.A.S. Nagar (Mohali), Punjab-160062, India.
Prajwal P
PP
Nandekar
Abhay T
AT
Sangamwar
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods / Q000592:standards; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D021281:Quantitative Structure-Activity Relationship
D000970:Antineoplastic Agents; D019363:Cytochrome P-450 CYP1A1