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Multitargeted Docking, DFT-Based Optimisation, Pharmacokinetics, and MD Simulation Reveal 6-Oxidopamine HBr as a
Yossef Saeed Alghamdi1, Mutaib M Mashraqi2, Ohud Alsalmi3
1Department of Biology, Turabah College, Taif University, Taif, 21944, Kingdom of Saudi Arabia.
Background:
Cervical cancer originates in the cervix, the lower part of the uterus, and results from the uncontrolled growth of abnormal cervical cells, forming malignant tumours. It poses a major global health challenge, calling for innovative drug design strategies to enhance treatment outcomes.
Methods:
In this study, we have screened the FDA-approved drug library against four proteins, MCM10, MCM6, DNA polymerase epsilon subunit-2, and TBK1, which are essential for DNA replication, DNA repair, and cellular signalling pathways, which are dysregulated in cervical cancer cells, leading to uncontrolled growth. We have used the multisampling algorithms for screening using HTVS, SP, and XP docking; identified 6- oxidopamine HBr (C8H12BrNO3), which is used to create a model of Parkinson's disease in animals, and obtained the docking score ranging from -5.057 to -8.871 Kcal/mol. The poses were filtered with MM\GBSA score ranging from -21.67 to -27.63 Kcal/mol. We performed QM-based DFT and pharmacokinetics studies and compared them with the standard values, suggesting that the compound can be used in cervical cancer proteins.
Results:
The P-L complex's interaction fingerprints have resulted in the most interacting residues, 4THR, 4SER, and 4LYS, showing the compound's interaction pattern.
Conclusion:
Further, the stability of 6-oxidopamine HBr in complex with each protein was evaluated with 100 ns MD simulation in the SPC water model in a neutralised state to analyse the deviation, fluctuations, and intermolecular interactions that have proven the compound to have a better inhibitory effect against each protein and that it can be used for cervical cancer; however, experimental validation is suggested before human use.
Insights
Researchers identified 6-oxidopamine HBr as a potential drug candidate for cervical cancer treatment. Molecular docking and simulations suggest it can inhibit key proteins involved in cancer cell growth.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Cervical cancer is a significant global health issue driven by uncontrolled cervical cell growth.
- Innovative drug design is crucial for improving cervical cancer treatment outcomes.
Purpose of the Study:
- To screen FDA-approved drugs for potential cervical cancer therapies.
- To identify compounds that inhibit key proteins regulating DNA replication, repair, and signaling in cervical cancer.
Main Methods:
- Utilized high-throughput virtual screening (HTVS, SP, XP docking) on an FDA-approved drug library.
- Screened against MCM10, MCM6, DNA polymerase epsilon subunit-2, and TBK1 proteins.
- Performed molecular mechanics with Generalized Born surface area (MM/GBSA) scoring, quantum mechanics-based density functional theory (DFT), and pharmacokinetic studies.
Main Results:
- Identified 6-oxidopamine HBr with significant docking scores (-5.057 to -8.871 Kcal/mol) and MM/GBSA scores (-21.67 to -27.63 Kcal/mol).
- Analysis of interaction fingerprints revealed key residues (THR, SER, LYS) involved in protein binding.
- Molecular dynamics (MD) simulations indicated the compound's stability and inhibitory potential against target proteins.
Conclusions:
- 6-oxidopamine HBr demonstrates promising inhibitory effects against cervical cancer-associated proteins.
- The compound's stability and interaction profile suggest its potential as a novel therapeutic agent.
- Experimental validation is recommended prior to clinical application in cervical cancer treatment.
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