Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study
Abstract
:1. Introduction
2. Results
2.1. In-Silico Screening
2.1.1. Target Identification Using Inverse Virtual Screening
2.1.2. Docking Studies and Molecular Dynamic Simulation Refinement
2.2. In Vitro Inhibitory Activity
2.3. Structure–Activity Relationship
3. Discussion
4. Materials and Methods
4.1. Library Construction
4.2. Bacterial Strains
4.3. Minimum Inhibitory Concentration (MIC) Assay
4.4. Checkerboard Microdilution Assay
4.5. Inverse Virtual Screening
4.6. Molecular Docking
4.7. Molecular Dynamic Simulation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Ligand | ∆GVina (Active and Allosteric Sites) | ∆G * KDEEP (Active and Allosteric Sites) | Hydrogen Bonding Interactions | Hydrophobic Interactions | ||
---|---|---|---|---|---|---|
Active Site | Allosteric Site | Active Site | Allosteric Site | |||
Myricetin (1) | >−7.0, −7.0 | >−7.0, −6.8 | ASN-464, TYR-519, GLN-521 | TYR-105, ASN-146 | TYR-446 | TYR-297 |
Quercetin (2) | −7.2, −7.2 | <−7.0, −7.1 | ASN-464, TYR-519, GLN-521 | TYR-105,TYR-297 | TYR-446 | - |
Kaempferol (3) | −7.6, <−7.0 | <−7.0, <−7.0 | SER-403 GLN-521 | ASN-146, ILE-144 | TYR-446 | - |
Apigenin (4) | −8.0, <−7.0 | −7.8, <−7.0 | SER-403, ASN-464, TYR-519, GLN-521 | ARG-298, GLY-296 | TYR-446 | - |
Chrysin (5) | −7.9, <−7.0 | −8.0, <−7.0 | SER-403, ASN-464, TYR-519, GLN-521, THR-600 | GLU-145, ASP-295 | TYR-446 | TYR-297 |
Hesperetin (6) | −7.8, −7.2 | −8.0, <−7.0 | SER-403, ASN-464, TYR-519, THR-600 | ILE-144, ASP-295 | TYR-446 | TYR-297 |
Astragalin (7) | −9.0, −8.1 | −8.7, −8.5 | SER-403, ASN-464, TYR-519, THR-600, GLN-613 | ILE-144, GLU-145, ASN-146, GLY-296 | - | TYR-105 |
Kaempferol 7-O-glucoside (8) | −9.1, −7.9 | −8.7, −8.4 | SER-403, SER-462, ASN-464, TYR-519 | TYR-105, ILE-144, GLU-145, ASN-146 | - | TYR-297 |
Quercitrin (9) | −9.0, −8.1 | −8.8, −8.3 | SER-403, ASN-464, TYR-519, THR-600, GLN-613 | ILE-144, GLU-145, ASN-146, GLY-296 | - | TYR-105 |
Rutin (10) | −9.4, −8.8 | −9.0, −8,7 | SER-403, ASN-464, TYR-519, THR-600, GLN-613 | TYR-105, ILE-144, GLU-145, ASN-146, GLY-296 | - | - |
Diosmin (11) | −9.6, −9.8 | −9.9, −9.2 | SER-403, SER-462, ASN-464, TYR-519, THR-600, GLN-613 | TYR-105, ILE-144, GLU-145, ASN-146, GLY-296 | - | - |
Hesperidin (12) | −9.5, −10.3 | −9.6, −9.9 | SER-403, SER-462, ASN-464, TYR-519, THR-600, GLN-613 | TYR-105, ILE-144, GLU-145, ASN-146, GLY-296, ARG-298, SER-306 | - | TYR-297 |
Silibinin A (13) | −8.8, −9.5 | −8.9, −9.3 | SER-403, SER-462, ASN-464, TYR-519, THR-600 | TYR-105, ILE-144, GLU-145, ASN-146, ASP-295, GLY-296, ARG-298, SER-306 | TYR-446 | TYR-105, TYR-297 |
Ampicillin (23) | >−7.0, >−7.0 | >−7.0, −7.1 | SER-462, ASN-464, TYR-519 | ILE-144, GLU-145, ASN-146 | - | TYR-297 |
Co-crystalized ligands (24 and 25) | −8.9 a, −9.1 b | −8.5 a, −9.0 b | SER-403 #, SER-462, ASN-464, GLN-521, SER-598, AlA-601 GLU-602, THR-600 | TYR-105, ILE-144, ASN-146, ARG-298 | TYR-446 | TYR-297 |
Tested Compound | MIC MSSA (µg/mL) | MIC MRSA (µg/mL) | FICI * | Inference |
---|---|---|---|---|
Myricetin (1) | 31.25 | 125 | 2 | Indifferent |
Quercetin (2) | 31.25 | 62.5 | 1.5 | Indifferent |
Kaempferol (3) | 31.25 | 62.5 | 1.5 | Indifferent |
Apigenin (4) | 15.62 | 31.25 | 1 | Additive |
Chrysin (5) | 15.62 | 15.62 | 1 | Additive |
Hesperetin (6) | 15.62 | 31.25 | 1 | Additive |
Astragalin (7) | 31.25 | 250 | 1.5 | Indifferent |
kaempferol 7-O-glucoside (8) | 31.25 | 250 | 1.5 | Indifferent |
Quercitrin (9) | 31.25 | 250 | 1.5 | Indifferent |
Rutin (10) | 125 | 250 | 0.625 | Synergistic |
Diosmin (11) | 31.25 | 250 | 0.31 | Synergistic |
Hesperidin (12) | 31.25 | 250 | 0.31 | Synergistic |
Silibinin A (13) | 62.5 | 250 | 0.31 | Synergistic |
Resveratrol (14) | 125 | 250 | 1.5 | Indifferent |
Caffeic acid (15) | >250 | 250 | 1.5 | Indifferent |
Sinapic acid (16) | 125 | >250 | 2 | Indifferent |
Rosmarinic acid (17) | >250 | >250 | 2 | Indifferent |
Gallic acid (18) | >250 | >250 | 2 | Indifferent |
Syringic acid (19) | >250 | >250 | 2 | Indifferent |
Trimethoxy benzoic acid (20) | >250 | >250 | 2 | Indifferent |
Gentisic acid (21) | >250 | >250 | 2 | Indifferent |
Benzyle anisate (22) | >250 | >250 | 2 | Indifferent |
Ampicillin (23) | 0.25 | 125 | - | - |
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Alhadrami, H.A.; Hamed, A.A.; Hassan, H.M.; Belbahri, L.; Rateb, M.E.; Sayed, A.M. Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study. Antibiotics 2020, 9, 562. https://doi.org/10.3390/antibiotics9090562
Alhadrami HA, Hamed AA, Hassan HM, Belbahri L, Rateb ME, Sayed AM. Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study. Antibiotics. 2020; 9(9):562. https://doi.org/10.3390/antibiotics9090562
Chicago/Turabian StyleAlhadrami, Hani A., Ahmed A. Hamed, Hossam M. Hassan, Lassaad Belbahri, Mostafa E. Rateb, and Ahmed M. Sayed. 2020. "Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study" Antibiotics 9, no. 9: 562. https://doi.org/10.3390/antibiotics9090562