In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries
Abstract
:1. Introduction
2. Results
2.1. The Analysis of Three Different QSAR Models
2.1.1. Construction and Verification of AutoQSAR Model
2.1.2. Construction and Verification of Naive Bayesian Model
2.1.3. Construction and Verification of Multiple Linear Regression Model
2.2. The Analysis of Molecular Docking
2.3. Covalent Docking
2.4. Scaffold Hopping
2.5. Analysis before and after Scaffold Hopping
2.6. Property Analysis of ADMET
2.7. The Analysis of RMSD and RMSF
2.8. Hydrogen Bond Analysis
3. Discussion
4. Materials and Methods
4.1. Compound Data Set Preparation
4.2. Protein Crystal Structure Preparation
4.3. The Construction of Three Different QSAR Models
4.3.1. Construction and Prediction of AutoQSAR Model
4.3.2. Construction and Prediction of Naive Bayesian Model
4.3.3. Construction and Prediction of Multiple Linear Regression Model
4.4. Structure-Based Virtual Screening
4.4.1. Molecular Docking Using Maestro
4.4.2. Molecular Docking Using MOE
4.4.3. Molecular Docking Using GOLD
4.5. Scaffold Hopping by Fragment Replacement
4.5.1. Molecular Processing
4.5.2. Optimization and Scoring
4.6. Prediction of ADMET Properties
4.7. Molecular Dynamics Simulations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Model Code | Score | S.D. | R2 | RMSE | Q2 |
---|---|---|---|---|---|
kpls_radial_20 | 0.7847 | 0.5998 | 0.8077 | 0.6184 | 0.8016 |
kpls_radial_5 | 0.7827 | 0.5797 | 0.8224 | 0.6101 | 0.8018 |
kpls_linear_20 | 0.7776 | 0.4559 | 0.8889 | 0.5662 | 0.8337 |
kpls_dendritic_20 | 0.7765 | 0.4491 | 0.8922 | 0.5648 | 0.8345 |
kpls_dendritic_34 | 0.7700 | 0.5324 | 0.8501 | 0.6018 | 0.8048 |
kpls_linear_5 | 0.7641 | 0.5264 | 0.8528 | 0.6050 | 0.8051 |
kpls_linear_34 | 0.7613 | 0.5377 | 0.8471 | 0.6116 | 0.7984 |
kpls_radial_13 | 0.7598 | 0.5320 | 0.8498 | 0.6110 | 0.8050 |
kpls_molprint2D_13 | 0.7501 | 0.5263 | 0.8545 | 0.6161 | 0.8017 |
kpls_dendritic_5 | 0.7500 | 0.5276 | 0.8522 | 0.6178 | 0.7967 |
Name | Pharmacophore Limitation | Filter Criteria | Before Scaffold Replacement | After Scaffold Replacement | Score |
---|---|---|---|---|---|
1008-1 | No | Weight < 600, SlogP [–4, 8], TPSA [40, 140], Score less than −12 | −18.4846 | ||
24428-35 | Weight<500, SlogP [–4, 8], TPSA [40, 140] | −13.1977 | |||
13058-2 | Weight < 500, SlogP [–4, 8], TPSA [40, 140], Score less than −10 | −10.7885 | |||
13058-3 | −13.0436 | ||||
13057-1 | Weight < 500, SlogP [–4, 8], TPSA [40, 140] | −11.2398 | |||
13057-2 | −11.4333 | ||||
13057-3 | −8.5368 | ||||
8171-3 | Weight < 500, SlogP [–4, 8], TPSA [40, 140] | −14.2391 | |||
8171-6 | −12.9634 | ||||
8171-7 | −12.4163 |
Compound | Hydrogen Bonds | π-π | Cation-π | Salt Bridge | Covalent Docking Score (kcal/mol) |
---|---|---|---|---|---|
P217564 | CYS223, GLY462 | - | - | ASP482, HIS464 | −5.583 |
13058 | TYR465, GLY463, GLY462, ASN218 | - | - | - | −5.866 |
13058-2 | CYS223, TYR465, GLY220, ASN218, ASP482 | - | - | ASP482 | −7.865 |
1008 | GLY220, GLY462, GLY483, SER457, HIS464 | - | - | - | −7.852 |
1008-1 | ASP459, ASP482, GLY220, TYR465, SER457 | - | - | - | −7.868 |
13057 | ASP482, GLY463 | HIS464 | HIS464 | - | −5.820 |
13057-3 | ASN460, ASP482, TYR465, GLY462 | - | - | ASP482 | −6.549 |
Compound | MDCK | BBB | VD | Fu | CYP2C19-Sub | H-HT | AMES | EC | EI |
---|---|---|---|---|---|---|---|---|---|
1008-1 | 8.34 × 10−6 | 0.071 | 1.813 | 29.79% | 0.053 | 0.116 | 0.442 | 0.003 | 0.006 |
13057-3 | 2.48 × 10−5 | 0.063 | 0.954 | 65.57% | 0.065 | 0.134 | 0.007 | 0.006 | 0.012 |
13058-2 | 3.48 × 10−6 | 0.355 | 1.011 | 67.65% | 0.064 | 0.062 | 0.007 | 0.003 | 0.019 |
P217564 | 3.15 × 10−5 | 0.016 | 1.196 | 1.65% | 0.423 | 0.547 | 0.947 | 0.003 | 0.043 |
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Tan, H.; Li, C.; Lai, T.; Luo, L. In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries. Mar. Drugs 2024, 22, 1. https://doi.org/10.3390/md22010001
Tan H, Li C, Lai T, Luo L. In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries. Marine Drugs. 2024; 22(1):1. https://doi.org/10.3390/md22010001
Chicago/Turabian StyleTan, Huiting, Chenying Li, Tianli Lai, and Lianxiang Luo. 2024. "In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries" Marine Drugs 22, no. 1: 1. https://doi.org/10.3390/md22010001