Molecular dynamics simulation studies for DNA sequence recognition by reactive metabolites of anticancer compounds.
The discovery of novel anticancer molecules 5F-203 (NSC703786) and 5-aminoflavone (5-AMF, NSC686288) has addressed the issues of toxicity and reduced efficacy by targeting over expressed Cytochrome P450 1A1 (CYP1A1) in cancer cells. CYP1A1 metabolizes these compounds into their reactive metabolites, which are proven to mediate their anticancer effect through DNA adduct formation. However, the drug metabolite-DNA binding has not been explored so far. Hence, understanding the binding characteristics and molecular recognition for drug metabolites with DNA is of practical and fundamental interest. The present study is aimed to model binding preference shown by reactive metabolites of 5F-203 and 5-AMF with DNA in forming DNA adducts. To perform this, three different DNA crystal structures covering sequence diversity were selected, and 12 DNA-reactive metabolite complexes were generated. Molecular dynamics simulations for all complexes were performed using AMBER 11 software after development of protocol for DNA-reactive metabolite system. Furthermore, the MM-PBSA/GBSA energy calculation, per-nucleotide energy decomposition, and Molecular Electrostatic Surface Potential analysis were performed. The results obtained from present study clearly indicate that minor groove in DNA is preferable for binding of reactive metabolites of anticancer compounds. The binding preferences shown by reactive metabolites were also governed by specific nucleotide sequence and distribution of electrostatic charges in major and minor groove of DNA structure. Overall, our study provides useful insights into the initial step of mechanism of reactive metabolite binding to the DNA and the guidelines for designing of sequence specific DNA interacting anticancer agents.
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER) S.A.S. Nagar, Punjab, India.
Khaled M
KM
Tumbi
Prajwal P
PP
Nandekar
Naeem
N
Shaikh
Siddharth S
SS
Kesharwani
Abhay T
AT
Sangamwar
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001711:Biotransformation; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry; D005419:Flavonoids / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D055672:Static Electricity; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism
C425784:2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; D000970:Antineoplastic Agents; D018736:DNA Adducts; D005419:Flavonoids; D007364:Intercalating Agents; D013844:Thiazoles; C413760:aminoflavone; D004247:DNA; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1
DNA; MESP; MM-PBSA; molecular docking; molecular dynamics simulations; molecular recognition; per-nucleotide energy decomposition; reactive metabolites