ANALYZING THE EFFECT OF NSSNPS IN CYP1A1 TOWARDS BENZOTHIAZOLES BINDING

Authors

  • Jemmy Christy h. Department of Bioinformatics, Sathyabama University, Chennai 119, Tamilnadu, India.
  • Preethi B. Department of Bioinformatics, Sathyabama University, Chennai 119, Tamilnadu, India.

Keywords:

CYP1A1, nsSNPs, Molecular dynamics, Cancer, 2-(4-Amino-3-methylphenyl) benzothiazole

Abstract

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.

Downloads

Download data is not yet available.

References

Bozina N, Bradamante V, Lovric M. Genetic polymorphism of metabolic enzymes P450 [CYP] as a susceptibility factor for drug response, toxicity, and cancer risk. Arh Hig RadaToksikol. 2009;60:21742.

Nebert DW, Russell DW. Clinical importance of the cytochromes P450.2002; Lancet 360:1155–1162.

Gonzalez FJ.Molecular genetics of the P-450 superfamily. Pharmacol Ther 1990;45:1–38.

Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer. 2006;6:94760.

Crofts F, Taioli E, Trachman J, Cosma GN, Currie D,Toniolo P, et al. Functional significance of different humanCYP1A1 genotypes. Carcinogenesis. 1994;15:2961-3.

Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA. Human Gene Mutation Database (HGMD):2003 update. Hum Mutat. 2003;7:577–581.

Cascorbi I, Brockmöller J, Roots I. A C4887A polymorphism in exon 7 of human CYP1A1:population frequency, mutation linkages, and impact on lung cancer susceptibility. Cancer Res. 1996;Nov 1;56 [21]:4965-9.

Cosma G, Crofts F, Taioli E, Toniolo P, Garte S. Relationship between genotype and function of the human CYP1A1 gene. J Toxicol Environ Health. 1993;40:309–16.

Garte S, Gaspari L, Alexandrie AK, Ambrosone C, Autrup H, Autrup JL, et al. Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev. 2001;10:1239–48.

Sergentanis TN, Economopoulos KP.Review Four polymorphisms in cytochrome P450 1A1 [CYP1A1] gene and breast cancer risk:a meta-analysis. Breast Cancer Res Treat. 2010 Jul;122[2]:459-69.

Chen S, Xue K, Xu L, Ma G, Wu J. Polymorphisms of the CYP1A1 and GSTM1 genes in relation to individual susceptibility to lung carcinoma in Chinese population. Mutat Res. 2001;458:41–7.

Garte S, Gaspari L, Alexandrie AK, Ambrosone C, Autrup H, Autrup JL, et al. Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev. 2001;10:1239–48.

Lin-Lin Wang, Yong Li, and Shu-Feng Zhou,A Bioinformatics Approach for the Phenotype Prediction of Nonsynonymous Single Nucleotide Polymorphisms in Human Cytochromes P450. Drug Metab Dispos May 2009;37:977-991.

Sai Ramesh A., Imran Khan, Md. Farhan, Padma Thiagarajan. Profiling Deleterious Non-synonymous SNPs of Smoker's Gene CYP1A1Cell Biochemistry and Biophysics. 2013;Volume 67, Issue 3, pp 1391-1396 15.

Eileen Brantley, Valentina Trapani, Michael C. Alley, Curtis D. Hose, Tracey D. Bradshaw, Malcolm F. G. Stevens, Edward A. Sausville, and Sherman F. Stinson,Fluorinated 2-[4-Amino-3-Methylphenyl]Benzothiazoles Induce Cyp1a1 Expression, Become Metabolized, And Bind To Macromolecules In Sensitive Human Cancer Cells. Drug Metab Dispos 2004;32:1392-1401.

Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K. dbSNP:the NCBI database of genetic variation. Nucleic Acids Res. 2001;Jan 1;29[1]:308-11.

Fiser A, Sali A. Modeller:generation and refinement of homology-based protein structure models. Methods Enzymol. 2003;374:461–491.

Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, et al. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res. 2003;31:3497–3500. doi:10.1093/nar/gkg500.

Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993;234:779–815.

Laskowski RA, Rullmannn JA, MacArthur MW, Kaptein R, Thornton JM. AQUA and PROCHECK-NMR:programs for checking the quality of protein structures solved by NMR. J Biomol NMR. 1996;8:477–486.

DeLano WL:The PyMOL Molecular Graphics System, Version 0.99. San Carlos, CA:DeLano Scientific;2002.

Guex, N. and Peitsch, M.C. SWISS-MODEL and the Swiss-PdbViewer:An environment for comparative protein modeling.Electrophoresis, 1997;18:2714-2723.

Laskowski. R.A.PDBsum:Summaries and analyses of PDB structures.NucleicAcidsResearch,29:221-222,2001

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK:AutoDock4 and AutoDockTools4:automated docking with selective receptor flexibility.J. Comput Chem 2009, 30:2785–2791.

Wang Y, Xiao J, Suzek TO, Zhang J, Wang J, Bryant SH.PubChem:a public information system for analyzing bioactivities of small molecules. Nucleic Acids Res. 2009;37:W623–33.

Accelrys Software Inc., Discovery Studio Modeling Environment, Release 4.0, San Diego:Accelrys Software Inc., 2013.

Wallace, A. C., R. A. Laskowski, and J. M. Thornton. LIGPLOT:a program to generate schematic diagrams of protein-ligand interactions. Protein Eng.1995;8:127-134.

Desmond Molecular Dynamics System, version 3.1;D. E. Shaw Research:New York, NY, USA, 2012.

Maestro-Desmond Interoperability Tools, version 3.1;Schrödinger:New York, NY, USA, 2012.

Gromiha MM, Ponnuswamy PK Prediction of protein secondary structures from their hydrophobic characteristics. Int J Pept Protein Res.1995;45:225–240.

Rose GD, Wolfenden R. Hydrogen bonding, hydrophobicity, packing, and protein folding. Annu Rev Biophys Biomol Struct 1993;22:381–415.

Yue P, Moult J. Identification and analysis of deleterious human SNPs. J Mol Biol.2006;356:1263–1274.

Wang Z, Moult J. SNPs, protein structure, and disease. Hum Mutat 2001;17:263–270.

Published

01-07-2014

How to Cite

Christy h., J., and P. B. “ANALYZING THE EFFECT OF NSSNPS IN CYP1A1 TOWARDS BENZOTHIAZOLES BINDING”. International Journal of Pharmacy and Pharmaceutical Sciences, vol. 6, no. 7, July 2014, pp. 552-7, https://www.innovareacademics.in/journals/index.php/ijpps/article/view/1759.

Issue

Section

Original Article(s)