IDENTIFICATION OF A NEW SMALL MOLECULE FROM TAXUS BACCATA PLANT AS A POTENTIAL INHIBITOR OF VIRB8 OF BRUCELLA BACTERIA BY HIGH-THROUGHPUT VIRTUAL SCREENING ON TRADITIONAL CHINESE MEDICINE DATABASE

Background and Aim:The type IV secretion system (T4SS) is one the most important virulence factor of Brucella. VirB8 is a central assembly factor for all type IV secretion systems. Thus, it can be a potential target for novel antimicrobial drugs.Methods:In this study, a database with more than 57,000 active compounds originating from medicinal plants of China was used for high-throughput virtual screening against VirB8. Ligand preparation was done by Discovery Studio 2017 to optimize valance, charges and tautomeric form created for each ligand which finally made the library with more than 229656 records. Afterward, receptor preparation was conducted on CLC Drug Discovery 4.0 to prepare the structure of 4AKZ. Active Site Mapping was used based on the previous reports to identify key catalytic residues. Docking was accomplished in a pipeline with an increasing level of precision including HTVS (output: 5731), SP (output: 54) and finally XP (output: 6) by Screen Ligands module in CLC Drug Discovery 4.0. To select the final candidate, the output of the XP step was re-evaluated using more sophisticated MM-GBSA scoring.Results:The compound 6439 that originated from Taxus baccata plant, was the best selection as ultimate hit for VirB8 inhibition. This molecule can strongly interact with key residues, Q144 and K182, of VirB8 via hydrogen bonding and ionic interactions.Conclusion:For the final evaluation, a Molecular Dynamics simulation will be conducted on this ligand and if a satisfactory result obtains, the ligand will be synthesized and in-vitro experiments will perform.

کلیدواژه ها:

Brucella ، High-Throughput Virtual Screening ، VirB8 ، Inhibitor