In-silico evaluation of Bismurrayaquinone-A phytochemical as a potential multifunctional inhibitor targeting dihydrofolate reductase: implications for anticancer and antibacterial drug development

Abstract

Dihydrofolate reductase (DHFR) has gained significant attention in drug development, primarily due to marked distinctions in its active site among different species. DHFR plays a crucial role in both DNA and amino acid metabolism by facilitating the transfer of monocarbon residues through tetrahydrofolate, which is vital for nucleotide and amino acid synthesis. This considers its potential as a promising target for therapeutic interventions. In this study, our focus was on conducting a virtual screening of phytoconstituents from the IMPPAT2.0 database to identify potential inhibitors of DHFR. The initial criterion involved assessing the binding energy of molecules against DHFR and we screened top 20 compounds ranging energy −13.5 to −11.4 (kcal/Mol) while Pemetrexed disodium bound with less energy −10.2 (kcal/Mol), followed by an analysis of their interactions to identify more effective hits. We prioritized IMPHY007679 (Bismurrayaquinone-A), which displayed a high binding affinity and crucial interaction with DHFR. We also evaluated the drug-like properties and biological activity of IMPHY007679. Furthermore, MD simulation was done, RMSD, RMSF, Rg, SASA, PCA and FEL explore the time-evolution impact of IMPHY007679 comparing it with a reference drug, Pemetrexed disodium. Collectively, our findings suggest that IMPHY007679 recommend further investigation in both in vitro and in vivo settings for its potential in developing anticancer and antibacterial therapies. This compound holds promise as a valuable candidate for advancing drug research and treatment strategies.

Communicated by Ramaswamy H. Sarma

Keywords:

• Dihydrofolate reductase
• phytoconstituents
• virtual screening
• molecular dynamic simulation
• free energy landscape

Acknowledgement

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through Large Groups Project under grant number (RGP.2/119/44).

Disclosure statement

No potential conflict of interest was reported by the authors

Author contributions

All the authors namely Lei Qian, Mohammad Khalid, Mohammed H. Alqarni, Sultan K. Alshmmari, Mohammad Ali Abdullah Almoyad, Shadma Wahab, Abdulrhman Alsayari, and Shao-Ji Li have contributed to conceptualization, investigation, methodology implementation, data analysis, and manuscript writing and review.

Data availability statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.