Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity
Abstract
:1. Introduction
- (1)
- Step 1 [1,8,9,10,11,13]: The mechanism of the coagulation cascade begins with coagulation on TF-bearing cells. Factor IX and VII, along with their respective co-factors, are responsible for the hydrolysis of factor X, leading to its conversion to its activated form Xa. The activated factor Xa is accountable for the dual breaking of prothrombin first at an arg-thr and then at an arg-ile bond, thereby generating active thrombin, which is a coagulation protease. A single factor X converts several prothrombin molecules, thus generating multiple thrombin molecules.
- (2)
- (3)
- Step 3 [1,8,9,10,11,13]: The third step involves “thrombin burst”, which occurs due to continuous generation of thrombin on the platelet surface, thereby leading to repeated cycles of mutual activation of factor X, IX and VII by each other. This thrombin burst through fibrin polymerization is vital for a thrombus formation.
2. Results
R2tr = 0.831, R2adj. = 0.83, RMSEtr = 0.476, CCCtr = 0.908, s = 0.478, F = 731.048, R2cv (Q2loo) = 0.829, RMSEcv = 0.479, CCCcv = 0.907, Q2LMO = 0.828, R2Yscr = 0.007, RMSEex = 0.526, R2ex = 0.783, Q2 − F1 = 0.782, Q2 − F2 = 0.782, Q2 − F3 = 0.794, CCCex = 0.874, R2 − ExPy = 0.783, R′o2 = 0.704, k′ = 0.996, 1 − (R2/R′o2) = 0.101, Ro2 = 0.782, k = 0.999, 1 − (R2 − ExPy/Ro2) = 0.001
3. Discussion
3.1. Mechanistic Interpretation of QSAR Model
3.2. Comparison of QSAR Results with Reported Crystal Structures
4. Materials and Methods
4.1. Data Collection & Curation
4.2. Calculation of Molecular Descriptors and Objective Feature Selection (OFS)
4.3. Splitting the Data Set into Training and External Sets and Subjective Feature Selection (SFS)
4.4. Building Regression Model and Its Validation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
SMILES | Simplified molecular-input line-entry system |
GA | Genetic algorithm |
MLR | Multiple linear regression |
QSAR | Quantitative structure−activity relationship |
WHO | World Health Organization |
ADMET | Absorption, distribution, metabolism, excretion, and toxicity |
OLS | Ordinary least square |
QSARINS | QSAR Insubria |
OECD | Organisation for Economic Co-operation and Development |
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S.N. | SMILES Notation | Ki (nM) | pKi (M) |
1 | COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN(C)C2=NCCO2)c1Cl | 0.007 | 11.155 |
2 | COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN(C)C2=NCCCO2)c1Cl | 0.012 | 10.921 |
3 | CCN(Cc1csc(C(=O)Nc2c(OC)cc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c1Cl)C1=NCCO1 | 0.012 | 10.921 |
4 | COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1ccc(-n2ccccc2=O)cc1 | 0.013 | 10.886 |
5 | COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN(C)C2=NCCS2)c1Cl | 0.024 | 10.62 |
1117 | C=Cc1cc(OC2CCOCC2)cc(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1 | 13,300 | 4.876 |
1118 | C#Cc1cc(O[C@@H]2CCOC2)cc(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1 | 15,300 | 4.815 |
1119 | CC(C)(C)OC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)c1cccc(C(=N)N)c1 | 16,000 | 4.796 |
1120 | CN1CC(C)(COc2ccc(C(=N)N)cc2)Oc2cc(N(Cc3ccccc3)C(=O)C(=O)O)ccc21 | 16,600 | 4.78 |
1121 | CCOC(=O)CCC(=O)N(Cc1ccccc1)c1ccc2c(c1)OC(C)(COc1ccc(C(=N)N)cc1)CN2C | 18,000 | 4.745 |
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Zaki, M.E.A.; Al-Hussain, S.A.; Masand, V.H.; Sabnani, M.K.; Samad, A. Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity. Int. J. Mol. Sci. 2021, 22, 8352. https://doi.org/10.3390/ijms22158352
Zaki MEA, Al-Hussain SA, Masand VH, Sabnani MK, Samad A. Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity. International Journal of Molecular Sciences. 2021; 22(15):8352. https://doi.org/10.3390/ijms22158352
Chicago/Turabian StyleZaki, Magdi E. A., Sami A. Al-Hussain, Vijay H. Masand, Manoj K. Sabnani, and Abdul Samad. 2021. "Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity" International Journal of Molecular Sciences 22, no. 15: 8352. https://doi.org/10.3390/ijms22158352