Screening of anticancer drugs against potential carcinogenic bacterial virulence proteins in colorectal cancer: An in silico approach.

Anaerobic bacteria induced colorectal cancer (CRC) represents a significant clinical concern. The understanding of cancer etiology has evolved significantly, from being predominantly viewed as genetically induced cancer to bacterial biofilm induced cancer. Despite the growing evidence linking bacterial virulence to tumor progression, the molecular interactions between bacterial biofilm proteins and anticancer drugs remain poorly understood. We explored the interaction of clinically used anticancer drugs (bevacizumab, capecitabine, fluorouracil, fruquintinib, leucovorin calcium, regorafenib, and tucatinib) with virulence proteins of oncomicrobes including Helicobacter pylori (cytotoxin-associated gene A), Fusobacterium nucleatum (Fusobacterium adhesion A), Bacteroides fragilis (Bfragilis toxin). Leucovorin calcium exhibited the highest binding affinity toward cytotoxin-associated gene A (-7.9 kcal/mol) through 7 hydrogen bonds. Similarly, regorafenib demonstrated strong interaction with Bfragilis toxin and Fusobacterium adhesion A, with binding affinities -8.6 and -6.5 kcal/mol, respectively, supported by multiple hydrogen and covalent bonds. Subsequent molecular dynamics simulations revealed low root mean square deviation and root mean square fluctuation values, indicating stable and compact drugs-protein interaction. Therefore, contributing to functional inactivation of bacterial virulence factors, thereby weakening bacterial colonization, biofilm formation, and events that sustain pro tumorigenic microenvironment. Overall, the present study provides computational evidence over anticancer drugs that may interact with bacterial virulence mechanisms implicated in anaerobic bacteria induced CRC, offering novel insights into therapeutic avenues capable of mitigating bacterial contributions in CRC initiation and progression. SIGNIFICANCE STATEMENT: The study focuses evaluating anticancer drugs targeting carcinogenic virulence proteins associated with bacterial biofilm mediated colorectal cancer.