High Throughput Virtual Screening of Chinese Medicinal Plant Database for Antagonist Discovery Against Human Toll-Like Receptor 4

Toll-like receptors are conserved parts of immune system in animals and humans. They have a trans- membrane domain and also an extracellular region composed of 18-25 copies of a Lucien-rich repeat (LRR). After encounter with a viral and bacterial ligand, a signaling pathway is started to sense pathogens and initiate of innate immune system responses against microbial components. TLR4 are expressed by many types of cells, including mac-rophages, dendritic cells, B cells, and certain epithelial cells. Because TLR4 has a pivotal role in inflammation response, identification of active pharmaceutical compounds which could active this receptor is very important.In this study over 57,000 active compounds originated from medicinal plants were used in high throughput vir-tual screening techniques against TLR4. Ligands preparation was done by BIOVIA Discovery Studio 2016 to optimized valance, charges and also create all tautomer form of each ligand which finally make the library with more than 229656 records. After that receptor preparation (4G8A) was performed to remove water molecules and to optimize the structures using LigPrep module in Schrodinger2015-2. Active Site Mapping was used based on previous reports to identify key catalytic residue. Docking was conducted with three levels precision including HTVS (with output 2463), SP (with output 1692) and finally XP (with output 216) by the Glide module of Schro-dinger 2015-2. The outputs of last docking step (XP) were subjected to re-ranking docking algorithm of MOE,CLC Drug Discovery, ICM-Pro and Schrodinger 2015-2. The best lead for TLR4 activation were picked out ac-cording to the average docking scores of the above mentioned software. The top binder was synthesized and used for in-vitro cell culture experiments which in preliminary result give some promising result.

کلیدواژه ها:

virtual screening ، Medicinal Plants ، TLR4