DESIGN AND DISCOVERY OF LOPHINE DERIVATIVES AS MULTI-TARGETING AGENTS BY MOLECULAR DOCKING, ADMET, MD SIMULATION AND PHARMACOPHORE ANALYSIS: A COMPUTATIONAL APPROACH

Year 2025, Volume: 9 Issue: 3, 1 - 24

Pujan Sasmal , Shyamal Kumar Biswas , Akash Koley , Rimpa Jana , Jagrity Biswas

Abstract

Background
Lophine is one of the new core moiety with substitution of three phenyl rings at 2nd, 4th, and 5th position of the imidazole. Lophine is not explored in development of drug molecules. In this research, we have designed 30 lophine derivatives with different substituted functional groups. The designed compounds were evaluated through different In-silico tools and softwares to check their properties for different biological receptors.
Methods
Molecular docking study was carried out on different receptors i.e. EGFR for anti-cancer, COX-1, and COX-2 for anti-inflammatory, fungal oxidoreductase for anti-fungal, bacterial DNA gyrase for anti-bacterial and TNF-α, which co-relates different type of inflammatory diseases. Further, ADMET of the top docked compounds were carried out in SwissADME and ProTox-II webserver. The MD simulation was carried out to check the stability of the compounds inside the binding pocket of the different proteins. Finally, the common pharmacophore was generated by PharmaGist web server.
Results
The molecular docking results revealed that the SAP-28 has significant binding energies -9.8, -9.6 and -10.0 kcal/mol against EGFR, fungal oxidoreductase, and TNF-α receptors respectively. SAP-26 has potent interaction -9.8 and -11.0 kcal/mol against EGFR and COX-2 receptors respectively. Whereas, SAP-25 and SAP-19 showed the best interaction for bacterial DNA gyrase (-8.9 kcal/mol) and COX-1 receptor (-9.7 kcal/mol) respectively. To enhance the acceptability top docked compounds, the ADME parameters along with toxicity analysis were carried out where all the compounds showed acceptable results. Furthermore, the stability of the protein-ligand complexes were determined by a 100 ns MD simulation analysis and compounds were found stable. The common pharmacophore was generated with the help of the top compounds in the PharmaGist web server.
Discussion
This In-silico study established that, various substitution on the phenyl ring present in the 2nd position of the imidazole such as 2-hydroxy, 2-methyl, 3-methyl, 4-pyridinyl etc. governing their ability to interact with diverse targets. The compound can contribute a major role in the development of different leads in future.

Keywords

Lophine, molecular docking, ADME, toxicity, MD simulation, pharmacophore, multi-target

References

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