Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
Abstract
:1. Introduction
2. Results and Discussion
2.1. Molecular Docking Analysis
2.2. Molecular Dynamics Simulation Analysis
2.2.1. Root Mean Square Deviation (RMSD)
2.2.2. Radius of Gyration (Rg)
2.2.3. Solvent Accessible Surface Area (SASA)
2.2.4. Root Mean Square Fluctuations (RMSFs)
2.3. MM–PBSA Binding Free Energy Analysis
2.4. Physicochemical Properties and Drug-Likeness
2.5. Pharmacokinetics and Toxicological Properties
2.6. Modelling Biological Predictions to Physicochemical Properties
3. Materials and Methods
3.1. Preparation of Ligand
3.2. Preparation of Protein
3.3. Grid Generation
3.4. Molecular Docking Studies
3.5. Molecular Dynamics Simulation
3.6. Binding Free Energy Calculation
3.7. Physicochemical, Drug-Likeness, Pharmacokinetic and Toxicokinetic Properties Prediction
3.8. Distance-Based Linear Modeling of Physicochemical Properties, COX-1 and -2 Binding, Pharmacokinetic and Toxicokinetic Predictions
4. 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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Ligand Name | XP Docking Score (kcal mol−1) | GLIDE Energy (kcal mol−1) | GLIDE Model (kcal mol−1) | GLIDE Ligand Efficiency |
---|---|---|---|---|
Aspirin | −2.80 | −26.25 | −33.12 | −0.21 |
Tyrindoxyl sulfate | −6.17 | −33.26 | −37.64 | −0.36 |
Tyrindoleninone | −6.85 | −32.49 | −37.17 | −0.52 |
6-Bromoisatin | −6.06 | −27.95 | −36.96 | −0.50 |
6,6′-Dibromoindirubin | −7.25 | −36.23 | 2.69 | −0.33 |
Ligand Name | XP Docking Score (kcal mol−1) | GLIDE Energy (kcal mol−1) | GLIDE Model (kcal mol−1) | GLIDE Ligand Efficiency |
---|---|---|---|---|
Aspirin | −6.87 | −31.43 | −41.06 | −0.52 |
Tyrindoxyl sulfate | −6.34 | −34.58 | −44.53 | −0.37 |
Tyrindoleninone | −7.17 | −29.27 | −30.7 | −0.55 |
6-Bromoisatin | −6.19 | −26.1 | −32.51 | −0.51 |
6,6′-Dibromoindirubin | −3.14 | −15.27 | 1.96 | −0.14 |
Parameters | Aspirin | Tyrindoxyl Sulfate | Tyrindoleninone | 6-Bromoisatin | 6,6′-Dibromoindirubin |
---|---|---|---|---|---|
IUPAC Name | 2-acetyloxybenzoic acid | (6-bromo-2-methylsulfanyl- 1H-indol-3-yl) hydrogen sulfate | 6-bromo-2-methylsulfanylindol-3-one | 6-bromo-1H-indole-2,3-dione | 6-bromo-2-(6-bromo-2-hydroxy-1H-indol-3-yl) indol-3-one |
Canonical SMILES | CC(=O)OC1=CC=CC= C1C(=O)O | CSC1=C(C2=C(N1)C= C(C=C2)Br)OS (=O)(=O)O | CSC1=NC2=C(C1=O)C= CC(=C2)Br | C1=CC2=C(C=C1Br) NC(=O)C2=O | C1=CC2=C(C=C1Br)NC(= C2C3=NC4=C(C3=O)C=CC (=C4)Br)O |
Physicochemical properties | |||||
Molecular formula | C9H8O4 | C9H8BrNO4S2 | C9H6BrNOS | C8H4BrNO2 | C16H8Br2N2O2 |
Molecular weight | 180.16 g/mol | 338.20 g/mol | 256.12 g/mol | 226.03 g/mol | 420.05 g/mol |
Fraction Csp3 | 0.11 | 0.11 | 0.11 | 0.00 | 0.00 |
Heavy atoms | 13 | 17 | 13 | 12 | 22 |
Aromatic heavy atoms | 6 | 9 | 6 | 6 | 15 |
Molar refractivity (MR) | 44.90 | 69.94 | 62.35 | 49.86 | 96.02 |
Topological polar surface area (TPSA) | 63.60Ų | 113.07 Ų | 54.73 Ų | 46.17 Ų | 65.45 Ų |
Lipinski violations | 0 | 0 | 0 | 0 | 0 |
Lipophilicity | |||||
iLOGP | 1.3- | 1.25 | 2.26 | 1.14 | 2.73 |
XLOGP3 | 1.19 | 2.64 | 2.60 | 1,33 | 0.91 |
MLOGP | 1.51 | 1.52 | 1.68 | 0.91 | 2.95 |
SILICOS-IT | 1.10 | 1.63 | 3.69 | 2.19 | 5.42 |
Water Solubility | |||||
Log S (ESOL) | −1.85 | −3.79 | −3.34 | −2.45 | −5.47 |
Qualitative solubility | Very soluble | Soluble | Soluble | Soluble | Moderately soluble |
Parameters | Aspirin | Tyrindoxyl Sulfate | Tyrindoleninone | 6-Bromoisatin | 6,6′-Dibromoindirubin |
---|---|---|---|---|---|
Absorption | |||||
Human intestinal absorption | 76.93% | 90.56% | 94.99% | 92.49% | 90.08% |
CaCo-2 permeability | 0.09 | 0.94 | 1.29 | 1.23 | 0.54 |
P-glycoprotein I inhibitor | No | No | No | No | No |
P-glycoprotein II inhibitor | No | No | No | No | No |
Distribution | |||||
Plasma protein binding (QPlogKhsa) | −0.75 | −0.41 | −0.45 | −0.61 | 0.33 |
VDss (human) | −1.71 | −1.85 | 0.21 | −0.03 | 0.40 |
Fraction unbound (human) | 0.48 | 0.49 | 0.30 | 0.44 | 0.04 |
Blood brain barrier (BBB) permeability | −0.33 | −0.77 | −0.04 | 0.36 | −0.15 |
Metabolism | |||||
CYP 2D6 Substrate | No | No | No | No | No |
CYP 2D6 Inhibitor | No | No | No | No | No |
Excretion | |||||
Total clearance | 0.72 | 0.17 | 0.26 | 0.10 | 0.23 |
Renal OCT2 substrate | No | No | No | No | Yes |
Toxicity Assays | |||||
AMES toxicity | No | No | No | No | No |
Hepato toxicity | No | No | No | No | No |
hERG I inhibitor | No | No | No | No | No |
Oral rat acute toxicity LD50 (mol/kg) | 2.28 | 1.33 | 2.47 | 2.42 | 2.48 |
(A) | Marginal Tests, p-Value | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Physico-Chemical Parameter | Cox 1 | Cox 2 | Intestinal Absorption | CaCo-2 Permeability | QPlog Khsa | VDss | Unbound Fraction | BBB Permeability | Total Clearance | Oral LD50 |
iLOGP | 0.146 | 0.155 | 0.716 | 0.945 | 0.069 | 0.193 | 0.042 | 0.876 | 0.986 | 0.373 |
XLOGP3 | 0.056 | 0.115 | 0.485 | 0.895 | 0.011 | 0.364 | 0.103 | 0.713 | 0.518 | 0.989 |
MLOGP | 0.194 | 0.181 | 0.945 | 0.585 | 0.088 | 0.596 | 0.1 | 0.715 | 0.923 | 0.5 |
SILICOS-IT | 0.062 | 0.065 | 0.353 | 0.791 | 0.04 | 0.128 | 0.013 | 0.667 | 0.576 | 0.362 |
Log S (ESOL) | 0.041 | 0.091 | 0.419 | 0.874 | 0.009 | 0.417 | 0.083 | 0.792 | 0.409 | 0.965 |
Molecular weight | 0.049 | 0.093 | 0.525 | 0.943 | 0.006 | 0.576 | 0.149 | 0.631 | 0.377 | 0.876 |
Fraction Csp3 | 0.813 | 0.094 | 0.885 | 1 | 0.415 | 0.289 | 0.498 | 0.273 | 0.507 | 0.628 |
Heavy atoms | 0.142 | 0.125 | 0.916 | 0.636 | 0.03 | 0.811 | 0.158 | 0.526 | 0.792 | 0.967 |
Aromatic heavy atoms | 0.149 | 0.087 | 0.953 | 0.728 | 0.056 | 0.813 | 0.209 | 0.608 | 0.589 | 1 |
Molar refractivity | 0.044 | 0.109 | 0.464 | 0.981 | 0.009 | 0.476 | 0.091 | 0.719 | 0.495 | 0.987 |
Topological polar surface area | 0.889 | 0.558 | 0.906 | 0.883 | 0.833 | 0.161 | 0.642 | 0.02 | 0.783 | 0.114 |
Human Intestinal Absorption | MLOGP, Log S, Molecular weight | 0.2 | ||||||||
CaCo-2 Permeability | iLOGP, MLOGP, Molecular weight | 1 | ||||||||
Plasma protein binding (QPlogKhsa) | iLOGP, SILICOS-IT, Aromatic heavy atoms | 1 | ||||||||
VDss (human) | XLOGP3, Heavy atoms, Aromatic heavy atoms | 1 | ||||||||
Unbound fraction (human) | iLOGP, MLOGP, Fraction Csp3 | 0.1 | ||||||||
Blood-brain barrier (BBB) permeability | iLOGP, Fraction Csp3, Heavy atoms | 0.95516 | ||||||||
Total clearance | iLOGP, SILICOS-IT, Fraction Csp3 | 0.999697 | ||||||||
(B) | BEST model | R2 | ||||||||
COX-1 | Log S, Molecular refractivity, Total polar surface area | 0.98852 | ||||||||
COX-2 | iLOGP, Heavy atoms, Aromatic heavy atoms | 0.99933 |
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Rahman, M.M.; Junaid, M.; Hosen, S.M.Z.; Mostafa, M.; Liu, L.; Benkendorff, K. Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition. Molecules 2021, 26, 6538. https://doi.org/10.3390/molecules26216538
Rahman MM, Junaid M, Hosen SMZ, Mostafa M, Liu L, Benkendorff K. Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition. Molecules. 2021; 26(21):6538. https://doi.org/10.3390/molecules26216538
Chicago/Turabian StyleRahman, Md. Mominur, Md. Junaid, S. M. Zahid Hosen, Mohammad Mostafa, Lei Liu, and Kirsten Benkendorff. 2021. "Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition" Molecules 26, no. 21: 6538. https://doi.org/10.3390/molecules26216538