Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Molecular Docking
2.2. Molecular Dynamics Simulation
2.2.1. Root-Mean-Square Deviation (RMSD) Parameter
2.2.2. Hydrogen Bond Interactions (H-Bond)
2.2.3. Radius of Gyration (Rg)
2.2.4. Root-Mean-Square Fluctuation (RMSF) Parameter
2.3. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA)
2.4. Ligand Efficiency Calculation and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME-Tox) Properties
3. Computational Protocol
3.1. Docking Procedure
3.2. Molecular Dynamics Simulation
3.3. Free Energy Calculations
3.4. Ligand Efficiency Calculations
3.5. ADME-Tox Properties
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Docking Pose-1 | Docking Pose-2 | Docking Pose-3 | ||||
---|---|---|---|---|---|---|
ΔGbinding | RMSD | ΔGbinding | RMSD | ΔGbinding | RMSD | |
Lig5H9-5DPF 1 | −8.2 | 0.94 | −7.7 | 1.80 | −7.5 | 2.36 |
Lig783-5DPF | −8.0 | 1.07 | −8.0 | 1.16 | −7.8 | 1.80 |
Lig1022-5DPF | −7.9 | 0.90 | −7.8 | 1.88 | −7.7 | 1.46 |
Lig1392-5DPF | −7.3 | 3.02 | −7.2 | 4.02 | −6.8 | 5.06 |
Lig2177-5DPF | −8.0 | 2.45 | −7.9 | 3.01 | −7.8 | 3.76 |
Lig3444-5DPF | −8.1 | 1.16 | −8.0 | 4.18 | −7.9 | 4.57 |
Lig6199-5DPF | −7.0 | 6.76 | −6.9 | 6.81 | −6.6 | 6.85 |
Complexes | RMSD (Å) | Number of H-Bond | Rg (Å) |
---|---|---|---|
Lig5H9-5DPF 1 | 1.11 ± 0.13 | 1.48 ± 1.68 | 5.36 ± 0.52 |
Lig783-5DPF | 0.93 ± 0.08 | 0.17 ± 0.54 | 3.56 ± 0.02 |
Lig1022-5DPF | 1.02 ± 0.11 | 0.09 ± 0.32 | 5.88 ± 0.86 |
Lig1392-5DPF | 1.10 ± 0.15 | 0.35 ± 0.82 | 4.25 ± 0.04 |
Lig2177-5DPF | 0.90 ± 0.07 | 0.46 ± 0.73 | 5.78 ± 0.29 |
Lig3444-5DPF | 0.98 ± 0.08 | 0.74 ± 1.26 | 3.87 ± 0.03 |
Lig6199-5DPF | 0.97 ± 0.08 | 0.05 ± 0.26 | 4.99 ± 0.14 |
Complexes | ∆Gbinding | ∆Eelect | ∆Evdw | ∆Gpolar | ∆GApolar |
---|---|---|---|---|---|
Lig5H9-5DPF 1 | −146.79 ± 8.30 | −150.45 ± 13.06 | −227.00 ± 7.61 | 254.72 ± 9.29 | −24.05 ± 0.74 |
Lig783-5DPF | −60.84 ± 11.32 | −24.72 ± 14.56 | −81.13 ± 0.29 | 55.27 ± 17.78 | −10.26 ± 0,84 |
Lig1022-5DPF | −114.11 ± 25.88 | −1.84 ± 5.19 | −120.97 ± 20.03 | 25.89 ± 25.87 | −17.12 ± 2.35 |
Lig1392-5DPF | −75.79 ± 11.25 | −23.69 ± 6.66 | −87.35 ± 8.27 | 46.35 ± 12.71 | −11.09 ± 1.40 |
Lig2177-5DPF | −37.06 ± 10.44 | −42.08 ± 10.52 | −63.36 ± 15.97 | 78.06 ± 17.56 | −9.07 ± 2.28 |
Lig3444-5DPF | −27.31 ± 11.72 | −7.94 ± 6.26 | −49.88 ± 20.82 | 36.92 ± 21.27 | −6.41 ± 2.67 |
Lig6199-5DPF | −88.56 ± 19.45 | −74.95 ± 15.19 | −159.04 ± 16.52 | 165.67 ± 33.93 | −20.23 ± 1.22 |
Ligands | MW (kDa) | Kd | clogP | LE | BEI | LLE | HBA | HBD | TPSA (Å2) | RB |
---|---|---|---|---|---|---|---|---|---|---|
Lig5H9 1 | 0.4855 | 9.78 × 10−7 | 2.71 | 0.248 | 12.37 | 3.29 | 8 | 5 | 163.87 | 16 |
Lig783 | 0.2723 | 1.37 × 10−6 | 2.60 | 0.400 | 21.52 | 3.26 | 2 | 2 | 40.46 | 0 |
Lig1022 | 0.4507 | 1.62 × 10−6 | 5.86 | 0.239 | 12.84 | −0.07 | 2 | 0 | 34.14 | 14 |
Lig1392 | 0.3574 | 4.46 × 10−6 | 2.81 | 0.280 | 14.96 | 2.54 | 3 | 3 | 74.35 | 5 |
Lig2177 | 0.4805 | 1.37 × 10−6 | 3.45 | 0.235 | 12.19 | 2.41 | 5 | 2 | 114.67 | 0 |
Lig3444 | 0.3561 | 1.15 × 10−6 | 2.31 | 0.368 | 16.66 | 3.62 | 3 | 3 | 74.72 | 0 |
Lig6199 | 0.5106 | 7.64 × 10−6 | 4.06 | 0.189 | 10.04 | 1.07 | 7 | 1 | 88.56 | 13 |
Properties | Oral Availability | Toxicity | |
---|---|---|---|
Lipinski Rules | Veber Rules | Pfizer 3/75 Rules | |
MW | ≤500 | - | - |
cLogP | ≤5 | - | ≤3 |
HBA | ≤10 | - | - |
HBD | ≤5 | - | - |
TPSA | - | ≤140 | ≤75 |
RB | - | ≤10 | - |
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Lamazares, E.; MacLeod-Carey, D.; Miranda, F.P.; Mena-Ulecia, K. Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents. Molecules 2021, 26, 386. https://doi.org/10.3390/molecules26020386
Lamazares E, MacLeod-Carey D, Miranda FP, Mena-Ulecia K. Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents. Molecules. 2021; 26(2):386. https://doi.org/10.3390/molecules26020386
Chicago/Turabian StyleLamazares, Emilio, Desmond MacLeod-Carey, Fernando P. Miranda, and Karel Mena-Ulecia. 2021. "Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents" Molecules 26, no. 2: 386. https://doi.org/10.3390/molecules26020386