Alternative use of droxidopa for treating cervical cancer: inhibiting transferase, cell cycle signalling, and transport proteins via multitarget docking, DFT, MD simulations, and binding free energy studies.

Cervical cancer develops due to the uncontrolled growth of abnormal cells in the cervix, mainly triggered by a persistent infection with high-risk types of human papillomavirus (HPV), a sexually transmitted virus. Factors that increase the risk include having multiple sexual partners, engaging in sexual activity at an early age, smoking, and a compromised immune system. Globally, it ranks as the fourth most prevalent cancer among women, with over 600000 new cases and 340000 deaths each year. The disease disproportionately impacts women in low- and middle-income countries, where access to screening and vaccination is often limited. Drug resistance emerges when cancer cells evade treatment through genetic mutations, altered targets, and efflux pump overexpression. Multitargeted docking identifies compounds interacting with multiple targets where a drug can inhibit crucial pathways, improving efficacy and reducing resistance chances. In this study, we examined Transferase, Cell Cycle Signalling, and Transport Proteins associated with PDB IDs 2WVI, 2B9R, 3VHX, and 3KND. These targets were subjected to multitargeted docking using an FDA-approved drug library. Droxidopa was identified as a multitargeted drug, with docking scores ranging from - 5.99 to - 11.37 kcal/mol and MM/GBSA scores between - 20.13 and - 43.00 kcal/mol. The interaction fingerprints identified the most interacted residues with counts are 4GLN, 4GLU, 3ARG, and 3TRP, and the Pharmacokinetics and DFT analysis favoured the compound's suitability. Furthermore, 5 ns (nanoseconds) WaterMap for hydration sites and 100 ns MD simulation in NPT ensemble at 330 K temperature have resulted in acceptable deviations, fluctuations, and many intermolecular interactions, and binding free energy computations have favoured droxidopa's use against cervical cancer-however, experimental studies are needed before its use including the in-vitro and in-vivo studies.