Identification of new potent agonists for toll-like receptor 8 by virtual screening methods, molecular dynamics simulation, and MM-GBSA

Abstract

Toll-like receptor 8 (TLR8), as an endosomal transmembrane receptor, plays a crucial role in the innate immune response to neoplasia and viruses. Previous studies have shown that TLR8 agonists e.g. Motolimod can be used to treat patients with last-stage cancer. In this study, in order to find new suitable ligands for TLR8, 16 PBD codes related to TLR8 complexes were collected to design the pharmacophore models using the Pharmit server. Then the PubChem, and ZINC databases were screened by them. Subsequently, the ADME-Tox features of the compounds were detected using FAF-Drugs4 and the selected compounds were docked to TLR8 (PDB: 3w3j). Molecular dynamics simulation was used to compare compounds with the best docking scores, with Motolimod in complex with TLR8. Finally, two compounds were identified, PubChem: 124126919 (A) and PubChem: 18559540 (B), each with advantages over Motolimod. As the RMSD results showed that compound A has very good flexibility, in terms of energy calculated using the MM-GBSA method, complex B and TLR8 showed the lowest energy level compared to the rest of the complexes. These observations suggest that these two compounds could be used as TLR8 agonists with the desired pharmacological features in future experimental studies.

Communicated by Ramaswamy H. Sarma

Keywords:

• Toll-like receptor 8
• virtual screening
• docking
• molecular dynamics simulation
• MM-GBSA

Acknowledgments

The authors would like to acknowledge the financial support of the University of Tehran under Grant Number 28669/06/16.

Also, the authors thank Dr. Zeynab Fakhar, a researcher at the University of the Witwatersrand, Johannesburg of South Africa for performing the MD simulation.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contributions

S.Gh. and Z.H. conceived the project. F.S did the experiments. S.Gh and F.S analyzed the data. Z.H and F.S wrote the manuscript. All authors read and approved the manuscript.

Data availability statement

No datasets were generated during the current study. However, all data that were analyzed or support the findings of this study are available from RCSB PDB, PubChem, and ZINC databases. In addition, the pharmit server and FAFDrugs4 were used as two devices for filtering the data.

Data repositories statement

2-amino-N, N-dipropyl-8-[4-(pyrrolidine-1-carbonyl) phenyl]-3H-1-benzazepine-4-carboxamide (Motolimod (VTX-2337) or MOT), N-{4-[5-oxo-4-(2-phenylethyl)-4H,5H-[1, 2, 4]triazolo[4,3-a]quinazolin-1-yl]phenyl}acetamide (PubChem: 18559540), and 2-[[3-(3,5-dimethylpyrazol-1-yl)phenyl]methyl]-7-methoxypyrazolo[1,5-c]quinazolin-5-amine (PubChem: 124126919) are two compounds that were introduced in the conclusion.

Additional information

Funding

This work was supported by the financial support of the University of Tehran under Grant Number 28669/06/16.