title: Understanding the Interactions of High-Mobility Group of Protein Domain B1 with DNA Adducts Generated by Platinum Anticancer Molecules Using In Silico Approaches.
abstract: Platinum coordination compounds having cis geometry are frequently prescribed for various types of cancers. Protein dysregulation is one of the major factors contributing towards cancer metastasis. Head and neck squamous cell carcinoma (HNSCC) is one of the cancers where platinum-based compounds are used either alone or in combination with radiation as therapy. The underlying interactions of these compounds with both DNA and proteins are crucial for the drug response. The compounds forms DNA adducts which are recognized by conserved, non-chromosomal high-mobility group box 1 (HMGB1) proteins. In the present study, we report the molecular dynamics simulations with the aim of understanding the behavior of platinum molecules that bind DNA. The binding pocket is identified using molecular docking approach. The sixteen mer stretch of the DNA-(d(CC(5IU)CTCTGGACCTTCC) * d(GGAAGGTCCAGAGAGG)) duplex containing G*G* is the major adduct of the anti-tumor molecule. We have performed comparison of inhibitory potential of the already known inhibitors of HNSCC against HMGB1-binding pocket using simulations and docking. Variations in the binding site are observed for these inhibitors-DNA-protein ternary complexes involving defined groups. We have validated our results using geometry-based docking transformations against the specific binding site as well as blind docking that involves complete protein for the identification of specific binding site. Effective dose of the compound reflects its activity. The interactions between DNA and HMGB1 are defined by hydrogen bonds and van der Waals contacts. However, the ternary complex stabilization is mediated by hydrogen bonding and hydrophobic interactions. Significant deviations are observed in the RMSD values. We have classified the inhibitors in two categories where group A compounds shows interactions against the HMGB1 domain box B and group B toward both boxes A and B. Experimental IC50 values corroborates with the binding energies of the compounds. We propose the predicted pattern of binding as specific for platinum inhibitors. These studies are a new addition to the existing structural-activity relationship-based pharmacophore generation with a potential for use in the treatment of head and neck squamous cell carcinoma. The compounds can be validated as lead molecules using in vitro and in vivo experiments.
authors.affiliation: Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, 201313, India. kamgauri@gmail.com.
authors.forename: Gauri
authors.initials: G
authors.lastname: Misra
authors.affiliation: Bioinformatics Centre, Biotech Park, Sector-G, Jankipuram, Lucknow, Uttar Pradesh, 226021, India. shiprabioinfo@gmail.com.|Excelra Knowledge Solutions Pvt. Ltd. (Gvk Informatics), Hyderabad, 500039, India. shiprabioinfo@gmail.com.
authors.forename: Shipra
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, 201313, India.
authors.forename: Neetu
authors.initials: N
authors.lastname: Jabalia
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013816:Thermodynamics; D018675:Toxicity Tests
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D024243:HMGB1 Protein; D010984:Platinum; D004247:DNA
keywords: Head and neck squamous cell carcinoma; High-mobility group protein; Molecular docking; Molecular dynamics simulations; Molecular interactions