ANALYZING THE EFFECT OF NSSNPS IN CYP1A1 TOWARDS BENZOTHIAZOLES BINDING
Keywords:
CYP1A1, nsSNPs, Molecular dynamics, Cancer, 2-(4-Amino-3-methylphenyl) benzothiazoleAbstract
Objective: CYP1A1 involved in biotransformation of carcinogenic polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines/amides (HAAs) and results in electrophilic reactive intermediates that leads to toxicity and cancer, thus influencing the fields of cancer research.Benzothiazole and its analogs are known for their anti-tumor activity because they act as potent aryl hydrocarbon receptor (AhR) agonist thus binds AhR and results in induction of CYP1A1 which forms DNA adduct and leads to cell death by activation of apoptotic mechanism. The main aim of this study is to extrapolate the relationship between nsSNPs of CYP1A1 and their effects in Benzothiazoles binding capability.
Methods: Computational analysis of deleterious mutations in CYP1A1 and their impact on its structure were as well as altered drug response to Benzothiazoles based drug DF 203, NSC 674495 were studied. Furthermore molecular dynamics simulation (MDS) approach was conducted to investigate conformational changes in the mutant protein structure with respect to its native conformation.
Results: Our studies revealed that 6 deleterious nsSNPs CYP1A1 have the impact on structural stability based on secondary structural patterns and molecular dynamics and altered drug response was seen in nsSNP rs2229150 (R93W) for the drug 2-(4-amino-3-methylphenyl) benzothiazole (DF 203, NSC 674495).
Conclusion: Our study would be helpful to understand the nsSNP effect on CYP1A1 which in turn leads to carcinogenesis as well as Benzothiazole (DF-203) binding affinity and designing individualized therapeutic treatments.
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