Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling
Abstract
:1. Introduction
2. Materials and Methods
2.1. Target Preparation
2.2. Binding Site Prediction
2.3. Ligand-Based Pharmacophore Virtual Screening
2.4. Retrieval and Preparation of Chemical Library for Pharmacophore-Based Screening
2.5. Pharmacophore-Based Virtual Screening of the Libraries
2.6. Validation of Pharmacophore Model and AutoDock Vina
2.6.1. Pharmacophore Model Validation
2.6.2. Validation of AutoDock Vina
2.7. Molecular Docking Studies of Chemical Entities with Good Pharmacophore Fit Scores
2.8. Characterisation of Mechanism of Binding
2.9. ADMET Properties and Drug-Likeness Assessment
2.10. Prediction of Biological Activity of Selected Compounds
2.11. Molecular Dynamics Simulation Analyses of Protein and Protein–Ligand Complexes
2.12. Parasite Culture and In Vitro Effect of Compounds on L. donovani Promastigotes
2.13. In Vitro Culture and Cell Viability Assay for Trypanosoma brucei brucei GUTat 3.1
3. Results and Discussion
3.1. Predictions of LdSMT Binding Site Residues
3.2. Pharmacophore Generation
3.3. Validation of Generated Pharmacophore Model
3.4. Validation of Docking Protocol
3.5. Pharmacophore-Based Virtual Screening of Library
3.6. Molecular Docking Analysis
3.7. Protein–Ligand Interaction
3.8. ADMET Profiling
3.9. Biological Activity Predictions of Selected Hit Compounds
3.10. MD Simulations Analyses
3.11. MM/PBSA Computation of Free Binding Energies
3.12. In Vitro Evaluation of Identified Hits against Leishmania donovani
4. Contribution to the Field
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound ID | Pharmacophore Fit Score | Compound ID | Pharmacophore Fit Score |
---|---|---|---|
STOCK6S-64941 | 59.39 | STOCK6S-14893 | 58.37 |
STOCK6S-43563 | 59.23 | STOCK6S-06707 | 58.24 |
STOCK6S-07535 | 59.19 | STOCK7S-11482 | 58.14 |
STOCK6S-33909 | 59.19 | STOCK6S-16994 | 58.05 |
STOCK6S-39547 | 59.18 | STOCK6S-64616 | 57.53 |
STOCK6S-19430 | 59.00 | STOCK6S-65229 | 57.44 |
STOCK7S-75883 | 58.89 | STOCK6S-63483 | 57.37 |
STOCK7S-14941 | 58.87 | STOCK6S-55084 | 57.33 |
STOCK6S-84928 | 58.85 | STOCK6S-65920 | 57.3 |
STOCK6S-47549 | 58.47 | STOCK6S-47366 | 57.15 |
Ligands | Binding Energy/kcal/mol | Binding Residues | |
---|---|---|---|
Hydrogen Bonds | Hydrophobic Bonds | ||
−8.7 | Asp25, Ala28, Asp31, Arg32, Phe307, Ala311 | ||
−8.2 | Arg15, Asp28, Arg227 | Leu13, Lys313 | |
−8.0 | Ser350 | Glu192, Phe194, Arg195, Lys351 | |
−7.9 | Glu178, Trp208, His226, Ile228 | ||
−7.8 | Asp281, Ser284 | Leu322 | |
−7.7 | Arg289, Arg295 | Tyr316, Glu320 | |
−7.6 | Ala28, Phe307, Val308, Ala311 | ||
−7.5 | Glu219, Glu229, Tyr275 | Trp208, Ile224, Lys225, Ile228, Ile272 | |
−7.5 | Thr338 | Phe93, Ile258 | |
−7.6 | Glu102, Gly200 | Phe100, Lys198, Pro199 | |
−5.3 | Arg309, Asn299, Gly294, Leu288 | ||
−5.0 | Asp31, Arg32, Val308, Arg309, Leu310 | Glu306 | |
−4.0 | Cys202 | Phe100, Met101, Asp104, Asp172, Pro199, Gly200, Thr201, Tyr343, Ile344 |
Compound ID | MW (g/mol) | NRB | MR | TPSA (Å2) | LogS | SC | BS | GI | BBB | vRoF |
---|---|---|---|---|---|---|---|---|---|---|
STOCK6S-06707 | 406.52 | 1 | 129.05 | 54.71 | −5.31 | Moderate | 0.55 | High | Yes | 0 |
STOCK6S-84928 | 342.36 | 3 | 88.22 | 67.14 | −3.39 | Soluble | 0.55 | High | Yes | 0 |
STOCK6S-65920 | 353.39 | 2 | 103.42 | 42.68 | −4.73 | Moderate | 0.55 | High | Yes | 0 |
STOCK6S-55084 | 407.36 | 3 | 103.46 | 42.68 | −5.27 | Moderate | 0.55 | High | No | 0 |
STOCK6S-64941 | 434.53 | 6 | 130.16 | 80.57 | −5.62 | Moderate | 0.55 | High | No | 0 |
STOCK6S-19430 | 428.52 | 4 | 127.41 | 81.01 | −4.01 | Moderate | 0.55 | High | No | 0 |
STOCK6S-14893 | 410.55 | 1 | 128.98 | 54.71 | −5.11 | Moderate | 0.55 | High | Yes | 0 |
STOCK6S-07353 | 282.31 | 5 | 78.96 | 38.06 | −3.03 | Soluble | 0.55 | High | Yes | 0 |
STOCK6S-16994 | 384.51 | 2 | 121.32 | 54.71 | −4.5 | Soluble | 0.55 | High | Yes | 0 |
22,26-Azasterol | 403.64 | 2 | 125.08 | 52.49 | −5.66 | Moderate | 0.55 | High | Yes | 1 |
Amphotericin B | 924.08 | 3 | 239.06 | 319.61 | −5.37 | Moderate | 0.55 | Low | No | 3 |
Miltefosine | 407.57 | 20 | 115.9 | 68.40 | −5.32 | Moderate | 0.55 | Low | No | 0 |
Paromomycin | 615.63 | 9 | 133.56 | 347.32 | −2.44 | Soluble | 0.55 | Low | No | 3 |
Ligand | DataWarrior Predictions | |||
---|---|---|---|---|
Tumorigenic | Mutagenic | Irritant | Reproductive Effect | |
STOCK6S-06707 | None | None | High | None |
STOCK6S-84928 | None | None | None | None |
STOCK6S-65920 | None | None | None | Low |
STOCK6S-55084 | None | None | None | Low |
STOCK6S-64941 | None | None | None | High |
STOCK6S-19430 | None | None | High | high |
STOCK6S-14893 | None | None | High | High |
STOCK6S-07353 | None | None | None | None |
STOCK6S-16994 | None | None | High | High |
22,26-Azasterol | None | None | None | None |
Amphotericin B | None | None | None | None |
Miltefosine | None | None | None | None |
Paromomycin | None | None | None | None |
Complex | ΔGvdW (kJ/mol) | ΔGele (kJ/mol) | ΔGpol,sol (kJ/mol) | ΔGSASA (kJ/mol) | ΔGbind (kJ/mol) |
---|---|---|---|---|---|
STOCKIN6S-O6707 | −232.978 ± 1.954 | −983.173 ± 4.875 | 863.728 ± 3.447 | −18.722 ± 2.602 | −371.146 ± 2.105 |
STOCKIN6S−84928 | −142.275 ± 5.679 | −3.390 ± 0.417 | 29.163 ± 2.101 | −13.223 ± 4.385 | −129.725 ± 4.799 |
STOCKIN6S-65920 | −217.243 ± 3.589 | −6.439 ± 1.576 | 90.570 ± 4.465 | −16.786 ± 1.646 | −149.899 ± 3.600 |
22,26-Azasterol | −186.874 ± 2.143 | −217.654± 0.546 | 199.212± 4.701 | −16.211 ± 1.632 | −221.527 ± 3.716 |
Compound | Leishmania donovani IC50 (μM) ± SD | Trypanosoma brucei (IC50) (μM) ± SD |
---|---|---|
STOCK6S-65920 | 23.5 ± 1.1 | 18.1 ± 1.4 |
STOCK6S-06707 | 21.9 ± 1.5 | NA |
STOCK6S-84928 | 118.3 ± 5.8 | 14.3 ± 2.0 |
Amphotericin B | 6.56 ± 0.06 | - |
Diminazene | - | 0.1 ± 0.02 |
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Sakyi, P.O.; Kwofie, S.K.; Tuekpe, J.K.; Gwira, T.M.; Broni, E.; Miller, W.A., III; Wilson, M.D.; Amewu, R.K. Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling. Pharmaceuticals 2023, 16, 330. https://doi.org/10.3390/ph16030330
Sakyi PO, Kwofie SK, Tuekpe JK, Gwira TM, Broni E, Miller WA III, Wilson MD, Amewu RK. Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling. Pharmaceuticals. 2023; 16(3):330. https://doi.org/10.3390/ph16030330
Chicago/Turabian StyleSakyi, Patrick O., Samuel K. Kwofie, Julius K. Tuekpe, Theresa M. Gwira, Emmanuel Broni, Whelton A. Miller, III, Michael D. Wilson, and Richard K. Amewu. 2023. "Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling" Pharmaceuticals 16, no. 3: 330. https://doi.org/10.3390/ph16030330
APA StyleSakyi, P. O., Kwofie, S. K., Tuekpe, J. K., Gwira, T. M., Broni, E., Miller, W. A., III, Wilson, M. D., & Amewu, R. K. (2023). Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling. Pharmaceuticals, 16(3), 330. https://doi.org/10.3390/ph16030330