Understanding the Interactions of High-Mobility Group of Protein Domain B1 with DNA Adducts Generated by Platinum Anticancer Molecules Using In Silico Approaches

AbstractPlatinum 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 bind ing 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 specif ic binding site. Effective dose of the co...
Source: Interdisciplinary Sciences, Computational Life Sciences - Category: Bioinformatics Source Type: research