Scutianine_f: a promising lead compound against brucella virb8
,1,* Milad lagzian
,2 Malihe mohammadi
1. Dept. of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan - Iran
2. Dept. of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan - Iran
3. Dept. of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan - Iran
Brucella virb t4ss is a key virulence factor that plays important roles in mediating intracellular survival and manipulating host immune response to infection. based on cell biological, genetic, and x-ray crystallographic data, virb8 was proposed to undergo multiple protein-protein interactions to mediate assembly of the translocation machinery. consequently, virb8 inhibition strongly attenuates pathogenicity and can be considered a target for novel antimicrobial drugs which is the objective of this study.
The primary chinese medicine database with more than of 60.000 plant-originated pharmaceutical compounds, was retrieved from tcm website at http://tcm.cmu.edu.tw and was used for high-throughput virtual screening against virb8. ligand preparation wase done by biovia discovery studio 2018 (dassault systèmes, france) and the database was checked against lipinski and veber rules to remove any less druggable molecules. subsequently, the aqueous solubility of the library was calculated. solubility is one of the most important parameters in drug design due to a strong correlation between it and the bioavailability of the drug. in this regard, any compound with values less than -6 (less soluble) and more than zero (too soluble) was discarded from further processing. subsequently, the rest of the compounds were processed with ligand preparation & ligprep modules of discovery studio 2018 and schrodinger suite 2017-1 respectively. in this step, the ionization state was corrected at ph 7.2, tautomers and isomers were generated for each ligand and bad valences were fixed. the outputs of both software were merged together and duplicate compounds were removed using discovery studio to create the final library. this library that contains 29419 compounds was used for virtual screening step.
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 for creating a reasonable constraint. docking was accomplished in a sequentially manner with an increasing level of iteration from 1000 (output: 2942), to 10.000 (output: 30) and finally to 100.000 (output: 3) by screen ligands module of clc drug discovery 4.0. to select the final candidate, the output of last step was re-evaluated using more realistic free energy of binding calculation.
Finally, scutianine_f that was originated from scutia buxifolia plant, was selected as the lead compound. this compound had the highest docking score (-81 kcal/mol) interestingly, this molecule with a c38h45n5o5 chemical formula and mw of 651 had an already described antibacterial activity against gram-positive bacteria such as staphylococcus aureus. this molecule can strongly interact with key residues, q144 and k182, of virb8 via hydrogen bonding and ionic interactions.
A round of steered molecular dynamics simulation for 100-ns were used to evaluate the final candidate compound.
Brucella, virtual screening, virb8, scutianine_f