FtsZ is an appealing target for the design of antimicrobial agent that can be used to defeat the multidrug-resistant bacterial pathogens. Pharmacophore modelling, molecular docking and molecular dynamics (MD) simulation studies were performed on a series of three-substituted benzamide derivatives. In the present study a five-featured pharmacophore model with one hydrogen bond acceptors, one hydrogen bond donors, one hydrophobic and two aromatic rings was developed using 97 molecules having MIC values ranging from .07 to 957 μM. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (R = .8319), cross validated coefficient (Q = .6213) and a high Fisher ratio (F = 103.9) with three component PLS factor. A good correlation between experimental and predicted activity of the training (R = .83) and test set (R = .67) molecules were displayed by ADHRR.1682 model. The generated model was further validated by enrichment studies using the decoy test and MAE-based criteria to measure the efficiency of the model. The docking studies of all selected inhibitors in the active site of FtsZ protein showed crucial hydrogen bond interactions with Val 207, Asn 263, Leu 209, Gly 205 and Asn-299 residues. The binding free energies of these inhibitors were calculated by the molecular mechanics/generalized born surface area VSGB 2.0 method. Finally, a 15 ns MD simulation was done to confirm the stability of the 4DXD-ligand complex. On a wider scope, the prospect of present work provides insight in designing molecules with better selective FtsZ inhibitory potential.
Background:
The widespread hazardous issue of antibiotics resistance can be overcome by the development of target based potent antibacterial agents. Filamentous temperature-sensitive mutant Z (FtsZ), a simpler structural prokaryotic homolog of eukaryotic cytoskeletal tubulin, was considered as a competent target in antibacterial drug discovery.
Objective:
The purpose of present work is to evaluate the antitubercular activity of virtual hits by funnel-shaped filtering with glide docking followed by MM-GBSA binding energy and molecular dynamics simulation. Pharmacokinetics and biochemical activity of the computationally screened virtual hits have been studied to focus their potential to inhibit the bacterial cell division.
Method:
The docking study was performed against the crystal structure of Staphylococcus aureus and Mycobacterium tuberculosis FtsZ protein with the hits obtained from High Throughput Virtual Screening using Glide module in Schrodinger. ADME profile and 50 ns molecular dynamics simulationstudies were performed using the Schrödinger suite. The minimal inhibitory concentration of the test compounds were determined bythe colorimetric method by Resazurin Microtiter plate Assay.
Results:
The binding of hit molecules T5427054 and 6M356S were mainly supported by van der Waals interaction and an electrostatic component of solvation energycomputed by MM-GBSA method. 50 ns MD simulation built stability and dynamic property of the best-docked complex T5427054/2Q1Y. Both the hit molecules displayed antimycobacterial activity with minimal inhibitory concentration 500 μg/mL.
Conclusion:
In this study, it is found that new screened hit molecules with better theoretical results could be preferred to use as antimycobacterial agents and further their structural modification might be improved antimycobacterial properties of hit molecules.
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