Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds
<p>(<b>A</b>) An illustration representing the role of Fts-Z in the Z-ring assembly pathway, emphasizing normal and interrupted cell division in bacteria; (<b>B</b>) Structure of Fts-Z protein from S. aureus (PDB ID-2VXY) in ribbons bound to GDP (in brown CPK). The T7 loop is in pink and α-H7 helix is in green. The blue-colored portion is the N-terminal and the green portion is the C-terminal. The figure was visualized in BIOVIA Discovery studio visualizer v21.1; (<b>C</b>) The binding sites present on the Fts-Z protein. (Figure generated through PDBSUM) [<a href="#B37-molecules-27-01907" class="html-bibr">37</a>].</p> "> Figure 2
<p>The figure shows the grid formed around the receptor Fts-Z (PDB ID 2VXY), taking the site map tool’s predictions. Site points (presented on grey surface) for the potential binding site (site-1). The site score was 0.911 with a size of 791. Dscore- was 1.028, Volume—558.061, HB don./acc.—1.401, Hydrophilic—0.185, Hydrophobic—0.464.</p> "> Figure 3
<p>Schematic figure showing steps followed during virtual screening of compounds.</p> "> Figure 4
<p>The 2D and 3D diagrams of docking poses. (<b>A-I</b>) 3D interaction diagram of Alpha dimorphecolic acid (5312830) with Fts-Z protein.; (<b>A-II</b>) 2D interaction diagram of Alpha dimorphecolic acid (5312830) with Fts-Z protein.; (<b>B-I</b>) 3D interaction diagram of Aphanorphine (189594) with Fts-Z protein. (<b>B-II</b>) 2D interaction diagram of Aphanorphine (189594) with Fts-Z protein.; (<b>C-I</b>) 3D interaction diagram of Circinamide (21601944) with Fts-Z protein. (<b>C-II</b>) 2D interaction diagram of Circinamide (21601944) with Fts-Z protein.; (<b>D-I</b>) 3D interaction diagram of Aeruginosin 102 A (10101474) with Fts-Z protein. (<b>D-II</b>) 2D interaction diagram of Aeruginosin 102 A (10101474) with Fts-Z protein.; (<b>E-I</b>) 3D interaction diagram of PC190723 (25016417) with Fts-Z protein. (<b>E-II</b>) interaction diagram of PC190723 (25016417) with Fts-Z protein.</p> "> Figure 4 Cont.
<p>The 2D and 3D diagrams of docking poses. (<b>A-I</b>) 3D interaction diagram of Alpha dimorphecolic acid (5312830) with Fts-Z protein.; (<b>A-II</b>) 2D interaction diagram of Alpha dimorphecolic acid (5312830) with Fts-Z protein.; (<b>B-I</b>) 3D interaction diagram of Aphanorphine (189594) with Fts-Z protein. (<b>B-II</b>) 2D interaction diagram of Aphanorphine (189594) with Fts-Z protein.; (<b>C-I</b>) 3D interaction diagram of Circinamide (21601944) with Fts-Z protein. (<b>C-II</b>) 2D interaction diagram of Circinamide (21601944) with Fts-Z protein.; (<b>D-I</b>) 3D interaction diagram of Aeruginosin 102 A (10101474) with Fts-Z protein. (<b>D-II</b>) 2D interaction diagram of Aeruginosin 102 A (10101474) with Fts-Z protein.; (<b>E-I</b>) 3D interaction diagram of PC190723 (25016417) with Fts-Z protein. (<b>E-II</b>) interaction diagram of PC190723 (25016417) with Fts-Z protein.</p> "> Figure 5
<p>Surface is added to Fts-Z protein (PDB ID-2VXY) on the basis of hydrophobicity, and ADMA compound (in green) is shown to be docked in the binding cavity and another zoom in figure is shown for interacting residues of the protein with ligand. Further Zoom in view of the ADMA compound and interacting residues from binding cavity. The visualization was done through Biovia Discovery Studio Visualizer.</p> "> Figure 6
<p>The RMSD (in Å) of Fts-Z protein (PDB ID- 2VXY) with ADMA (ligand) compound during 100 ns MD trajectory. The fluctuations of both the ligand and the receptor were in an acceptable range. Fts-Z protein (in green) fluctuation was within 2 Å, achieving stability towards the end of the simulation, and that of ligand (in maroon) with respect to protein and its binding pocket was also not fluctuating significantly showing a stabler confirmation.</p> "> Figure 7
<p>The Root Mean Square Fluctuation (RMSF) of Fts-Z protein (PDB ID-2VXY) throughout 100 ns molecular dynamic simulations showing local fluctuations along with the receptor.</p> "> Figure 8
<p>(<b>A</b>) Two-dimensional diagram of contacts made more than 9% of simulation time between ADMA (ligand) and Fts-Z (PDB ID-2VXY) (receptor) in 100-ns molecular dynamics. Gln 192 showed a contact time of 110% because it had multiple interactions of a single type with ADMA atoms. (<b>B</b>) The plot represents the interaction of the ADMA with 2VXY residues in simulation. (<b>C</b>) A timeline representation of residues interacting with the ligand along with density in each trajectory frame.</p> "> Figure 9
<p>Ligand properties—Root mean square deviation (RMSD) of the ligand with respect to the reference conformation; rGyr (Measure of Extendedness of ligand); intraHB; MolSA; SASA; PSA.2.5. In-vitro Validation of Lead Compound.</p> "> Figure 10
<p>Zone of inhibition against <span class="html-italic">Bacillus subtilis</span> (MTCC 441): Muller Hinton Agar plate, (<b>A</b>) well size: 16.14 mm for Methanolic extract of <span class="html-italic">Oscillatoria</span> biomass (100 µgmL<sup>−1</sup>). (<b>B</b>) 23.12 mm for Alpha dimorphecolic acid (5 µgmL<sup>−1</sup>) 21.33 mm for Polymyxin B-sulphate (5 µgmL<sup>−1</sup>). Zone size in mm was recorded after 24 h of incubation time at 37 °C.</p> "> Figure 11
<p>Minimum inhibitory concentration of Methanolic extract of <span class="html-italic">Oscillatoria</span> against <span class="html-italic">Bacillus subtilis</span> (MTCC 441) Muller Hinton agar broth tubes A to K dilution range from 1024 to 1 µgmL<sup>−1</sup>. A—1024 µgmL<sup>−1</sup>, B—512 µgmL<sup>−1</sup>, C—256 µgmL<sup>−1</sup>, D—128 µgmL<sup>−1</sup>, E—64 µgmL<sup>−1</sup>, F—32 µgmL<sup>−1</sup>, G—16 µgmL<sup>−1</sup>, H—8 µgmL<sup>−1</sup>, I—4 µgmL<sup>−1</sup>, J—2 µgmL<sup>−1</sup>, K—1 µgmL<sup>−1</sup>.</p> "> Figure 12
<p>Minimum inhibitory concentration of Alpha dimorphecolic acid against <span class="html-italic">Bacillus subtilis</span> (MTCC 441) Muller Hinton agar broth tubes A to K dilution range from 1024 to 1 µgmL<sup>−1</sup>. A—1024 µgmL<sup>−1</sup>, B—512 µgmL<sup>−1</sup>, C—256 µgmL<sup>−1</sup>, D—128 µgmL<sup>−1</sup>, E—64 µgmL<sup>−1</sup>, F—32 µgmL<sup>−1</sup>, G—16 µgmL<sup>−1</sup>, H—8 µgmL<sup>−1</sup>, I—4 µgmL<sup>−1</sup>, J—2 µgmL<sup>−1</sup>, K—1 µgmL<sup>−1</sup>.</p> "> Figure 13
<p>Minimum inhibitory concentration of Polymyxin B sulphate against <span class="html-italic">Bacillus subtilis</span> (MTCC 441) Muller Hinton agar broth tubes A to K dilution range from 1024 to 1 µgmL<sup>−1</sup>. A—1024 µgmL<sup>−1</sup>, B—512 µgmL<sup>−1</sup>, C—256 µgmL<sup>−1</sup>, D—128 µgmL<sup>−1</sup>, E—64 µgmL<sup>−1</sup>, F—32 µgmL<sup>−1</sup>, G—16 µgmL<sup>−1</sup>, H—8 µgmL<sup>−1</sup>, I—4 µgmL<sup>−1</sup>, J—2 µgmL<sup>−1</sup>, K—1 µgmL<sup>−1</sup>.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Preparation of Receptor and Its Binding Site
2.2. Virtual Screening and Molecular Docking
2.3. ADME Analysis Using Qik Prop Module
2.4. Molecular Dynamics and Simulation
3. Discussion
4. Materials and Methods
4.1. Target and Ligands Retrieval
4.2. Preparation of Ligands and ADME Analysis
4.3. Preparation of Receptor and Its Binding Site
4.4. Virtual Screening and Molecular Docking
4.5. Binding Free Energy Calculation
4.6. Molecular Dynamics and Simulation
4.7. In Vitro Validation of Lead Compound
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Bioactive Molecules | Docking Score (Kcalmol−1) | MMGBSA-dG Binding (Kcalmol−1) | Interactions (Hydrogen Bonds) | ∆G (Kcalmol−1) [std] | Lig. Efficiency (Kcalmol−1) | Compounds Reported in |
---|---|---|---|---|---|---|
Alpha di-morphecolic acid (5312830) | −6.574 | −44.12 | Arg 29, Asn 33, Asn 299 | −8.52 [−0.35] | −0.41 | Oscillatoria redekei |
Aphanorphine (189594) | −6.010 | − | Asn 33, Ile 298 | −5.45 [−0.35] | −0.36 | Aphanizomenon flos aquae |
Circinamide (21601944) | −7.366 | − | Arg 29, Asn 33, Glu 34, Glu 305 | −7.00 [−0.36] | −0.26 | Anabeana circinalis |
Aeruginosin 102 A (10101474) | −8.666 | − | Arg 29, Asn 33, Asp 174, Ile 228 | −8.23 [−0.51] | −0.16 | Microcyctis viridis |
PC 190723 (2501641) | −4.135 | −53.36 | Asp 33, Leu 206, Ile 298 | −7.68 [−0.52] | −0.33 | Known Inhibitor |
Top Hit | Acceptable Range | Compound ID | ||
---|---|---|---|---|
5,312,830 | 189,594 | 10,101,474 | ||
mol MW (gMol−1) | <500 | 296.4 | 203.28 | 386.5 |
Donor HB | 0.0–5.0 | 1 | 0 | 1 |
Accpt HB | 2.0–20.0 | 2.75 | 3.50 | 5.75 |
QPlog Poct | 8.0–35 | 10.267 | 12.999 | 18.416 |
QPlog Pw | 4.0–45.0 | 5.804 | 9.579 | 5.53 |
QPlog Po/w | −2.0–6.5 | 1.972 | 3.654 | 2.881 |
QPlog S | −6.5–0.5 | −1.751 | −5.559 | −3.646 |
QPlog HERG | below −5 | −4.01 | −5.967 | −5.298 |
QPP Caco | <25 poor and >500 great | 729.418 | 1059 | 1180 |
QP LogBB | −3.0–1.2 | 0.465 | −0.83 | −0.61 |
QPP MDCK | <25 poor and >500 great | 389.156 | 526 | 1275 |
QPLog Khsa | −1.5–1.5 | 0.079 | 0.449 | –6.288 |
QPLog Kp | −8.0–1.0 | −4.142 | −2.147 | −1.761 |
PHOA | >80% is strong and <25% is weak | 89.734 | 100 | 100 |
Ro5 | Max., 4.0 | 0 | 0 | 0 |
Test Organism | Assays | Lead Compound | Known Inhibitor | Oscillatoria Biomass | |
---|---|---|---|---|---|
Alpha di Morphecolic Acid | Aphanorphine | Polymyxin B-Sulphate | Methanol Extracts | ||
B. subtilis (MTCC-441) | Agar Well diffusion assay (Zone of Inhibition in mm) | 23.12 ± 0.1 | 0.0 Nil | 21.33 ± 0.47 | 16.14 ± 0.6 |
MIC (µgmL−1) | 512 | NC | 256 | 1024 |
Concentration in (µgmL−1) | MIC (µgmL−1) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
1024 | 512 | 256 | 128 | 64 | 32 | 16 | 8 | 4 | 2 | 1 | ||
Methanolic Extract | − | + | + | + | + | + | + | + | + | + | + | 1024 |
Alpha Di Morphecolic Acid | − | − | + | + | + | + | + | + | + | + | + | 512 |
Polymyxin B Sulfate | − | − | − | + | + | + | + | + | + | + | + | 256 |
Aphanorphine | + | + | + | + | + | + | + | + | + | + | + | >1024 |
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Gurnani, M.; Rath, P.; Chauhan, A.; Ranjan, A.; Ghosh, A.; Lal, R.; Mukerjee, N.; Aljarba, N.H.; Alkahtani, S.; Rajput, V.D.; et al. Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds. Molecules 2022, 27, 1907. https://doi.org/10.3390/molecules27061907
Gurnani M, Rath P, Chauhan A, Ranjan A, Ghosh A, Lal R, Mukerjee N, Aljarba NH, Alkahtani S, Rajput VD, et al. Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds. Molecules. 2022; 27(6):1907. https://doi.org/10.3390/molecules27061907
Chicago/Turabian StyleGurnani, Manisha, Prangya Rath, Abhishek Chauhan, Anuj Ranjan, Arabinda Ghosh, Rup Lal, Nobendu Mukerjee, Nada H. Aljarba, Saad Alkahtani, Vishnu D. Rajput, and et al. 2022. "Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds" Molecules 27, no. 6: 1907. https://doi.org/10.3390/molecules27061907