Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Diversity Analysis of Dataset(s)
2.2. Molecular Docking
2.3. Analysis of BFE
2.4. Derived QSAR Models and Their Validation
2.5. Evaluation of Novel Designed smHDAC8 Inhibitors
3. Materials and Methods
3.1. Dataset Source, Preparation and Analysis
3.1.1. Dataset
3.1.2. Calculation of Molecular Descriptors and Dataset Diversity Analysis
3.2. Molecular Docking
3.2.1. Ligand Preparation
3.2.2. Protein Preparation
3.2.3. Grid Generation and Docking
3.3. Binding Free Energy (BFE) Calculations
3.3.1. Ligand and Ligand–Protein Complex Preparation
3.3.2. MM-PB/GBSA and QM/MM Based BFE Prediction
3.4. Quantitative Structure–Activity Relationship (QSAR) Model Development and Selection
3.5. Test Set Prediction
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Name | Compound Code * | Scaffold | R1 | R2 | smHDAC8 IC50 (nM) | pIC50-smHDAC8 | GLIDE SP_Score |
---|---|---|---|---|---|---|---|
TH100 | 13r | A | methoxy | 4-ethoxyphenyl | 305 ± 35 | 6.52 | −7.14 |
TH101 | 13s | A | methoxy | benzyl | 183 ± 39 | 6.74 | −7.51 |
TH104 | 13z | A | chloro | 2,4-dichlorophenyl | 191 ± 17 | 6.72 | −7.20 |
TH31 | 13a | A | hydrogen | phenyl | 468 ± 79 | 6.33 | −8.52 |
TH33 | 13b | A | methyl | phenyl | 154 ± 0.03 | 6.81 | −7.48 |
TH39 | 13c | A | methoxy | phenyl | 135 ±0.03 | 6.87 | −7.60 |
TH60 | 13k | A | methyl | 2-quinolyl | 96 ± 13 | 7.02 | −7.04 |
TH61 | 13e | A | chloro | phenyl | 67 ± 10 | 7.17 | −7.31 |
TH65 | 13l | A | methoxy | 4-biphenyl | 293 ±35 | 6.53 | −7.35 |
TH66 | 13h | A | ethoxy | phenyl | 129 ± 8 | 6.89 | −7.43 |
TH67 | 13i | A | propoxy | phenyl | 267 ± 49 | 6.57 | −7.51 |
TH68 | 13n | A | methoxy | 4-chlorophenyl | 146 ± 4 | 6.84 | −7.34 |
TH69 | 13m | A | methoxy | 4-methoxyphenyl | 106 ± 18 | 6.97 | −7.31 |
TH74 | 13t | A | chloro | 4-methoxyphenyl | 147 ± 5 | 6.83 | −7.65 |
TH75 | 13f | A | bromo | phenyl | 150 ± 9 | 6.82 | −7.41 |
TH76 | 13d | A | fluoro | phenyl | 178 ± 8 | 6.75 | −7.28 |
TH83 | 13j | A | isopropoxy | phenyl | 220 ± 56 | 6.66 | −8.58 |
TH85 | 13o | A | methoxy | 2-chlorophenyl | 351 ± 16 | 6.45 | −7.22 |
TH86 | 13p | A | methoxy | 2,4-dichlorophenyl | 122 ± 19 | 6.92 | −7.98 |
TH92 | 13za | A | ethoxy | 4-biphenyl | 92 ± 26 | 7.04 | −8.58 |
TH93 | 13x | A | chloro | 4-chlorophenyl | 235 ± 10 | 6.63 | −7.36 |
TH94 | 13g | A | trifluoromethyl | phenyl | 140 ± 8 | 6.86 | −7.10 |
TH95 | 13q | A | methoxy | 3-biphenyl | 290 ± 20 | 6.54 | −7.28 |
TH96 | 13y | A | chloro | 4-nitropheny | 394 ± 50 | 6.40 | −7.06 |
TH77 | 13u | A | chloro | 3-benzyloxyphenyl | 378 ± 45 | 6.42 | −9.49 |
TH78 | 13v | A | chloro | 3-phenoxyphenyl | 396 ± 43 | 6.40 | −9.55 |
TH81 | 13w | A | chloro | 4-phenoxyphenyl | 620 ± 70 | 6.21 | −8.85 |
TH58 | 14a | - | - | - | 8210 ± 1300 | 5.09 | −7.51 |
TH36 | 10c | - | - | - | 1722 ± 910 | 5.76 | −7.41 |
TH70 | 15a | - | - | - | 268 ± 21 | 6.57 | −7.34 |
TH71 | 16a | - | - | - | 485 ± 158 | 6.31 | −7.58 |
TH28 | 10a | B | hydrogen | benzyl | 1040 ± 250 | 5.98 | −7.15 |
TH32 | 10b | B | hydrogen | cyclohexyl | 3630 ± 620 | 5.44 | −6.80 |
TH35 | 10e | B | methyl | cyclohexyl | 600 ± 196 | 6.22 | −7.16 |
Model Number | Method | Frame | Number of Molecules | lm | LOOCV | Leave_3out CV | 3fold CV | Outlier | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
r2 | RMSE | q2 | QMSE | q2 | QMSE | q2 | QMSE | |||||
1 | 34 | 0.01 | 0.44 | - | - | - | - | - | - | |||
6 | AM1/GB1 | Emin2 | 34 | 0.41 | 0.34 | 0.30 | 0.37 | - | - | - | - | |
7 | AM1/GB1 | Emin2 | 34 | 0.51 | 0.31 | 0.38 | 0.35 | - | - | - | - | |
22 | GBHCT (igb = 1) | Emin2 | 34 | 0.31 | 0.37 | 0.13 | 0.42 | - | - | - | - | |
23 | GBHCT (igb = 1) | Emin2 | 34 | 0.51 | 0.31 | 0.32 | 0.36 | - | - | - | - | |
33 | GBOBC (igb = 2) | Emin1 | 33 | 0.30 | 0.37 | 0.19 | 0.40 | - | - | - | - | |
34 | GBOBC (igb = 2) | Emin1 | 34 | 0.46 | 0.32 | 0.33 | 0.36 | - | - | - | - | |
48 | GBOBC (igb = 5) | Emin1 | 34 | 0.31 | 0.36 | 0.20 | 0.40 | - | - | - | - | |
49 | GBOBC (igb = 5) | Emin1 | 34 | 0.47 | 0.32 | 0.34 | 0.36 | - | - | - | - | |
65 | GBn (igb = 8) | Emin2 | 34 | 0.19 | 0.40 | 0.02 | 0.48 | - | - | - | - | |
77 | PB-mbondi | Emin2 | 34 | 0.27 | 0.38 | 0.08 | 0.43 | - | - | - | - | |
94 | PB-bondi | MD51-100 | 34 | 0.45 | 0.33 | 0.36 | 0.35 | 0.39 | 0.36 | 0.38 | 0.36 | |
95 | PB-bondi | MD51-100 | 34 | 0.61 | 0.27 | 0.53 | 0.30 | 0.55 | 0.30 | 0.54 | 0.31 | |
96 | PB-bondi | MD51-100 | 33 | 0.62 | 0.22 | 0.53 | 0.25 | 0.56 | 0.25 | 0.54 | 0.26 | TH58 |
97 | PB-bondi | MD51-100 | 31 | 0.73 | 0.19 | 0.66 | 0.22 | 0.70 | 0.21 | 0.69 | 0.22 | TH58, TH70, TH74 |
105 | PB-PARSE | Emin2 | 34 | 0.17 | 0.40 | 0.01 | 0.46 | - | - | - | - | |
117 | PM3/GB1 | Emin2 | 34 | 0.37 | 0.35 | 0.26 | 0.38 | - | - | - | - | |
118 | PM3/GB1 | Emin2 | 34 | 0.52 | 0.31 | 0.41 | 0.34 | - | - | - | - |
Compound Number | Compoud Code | Scaffold | R1 | R2 | smHDAC8_IC50 nM- | pIC50_exp | pIC50_pred | Res a (Exp_pIC50-Pred_pIC50) | Res b Avg_Exp_pIC50-Pred_pIC50 | Glide SP_Score |
---|---|---|---|---|---|---|---|---|---|---|
1 | AT_T4 | A | methoxy | 9H-fluoren-1-yl | 163 ± 17 | 6.79 | 7.01 | −0.22 | −0.44 | −9.20 |
2 | SD14 | A | methoxy | 3-methyl-1,2,3,4-tetrahydro-ɣ-carbolin-8-yl | 197 ± 19 | 6.71 | 6.64 | 0.06 | −0.07 | −9.24 |
3 | TH112 | A | ethoxy | 2,4-dichlorophenyl | 103 ± 7 | 6.99 | 6.77 | 0.22 | −0.20 | −8.99 |
4 | TH117 | A | chloro | 4-biphenyl | 404 ± 90 | 6.39 | 6.42 | −0.03 | 0.15 | −8.69 |
5 | TH119 | A | methanethiolyl | 4-biphenyl | 101 ± 7 | 6.99 | 6.68 | 0.31 | −0.11 | −8.47 |
6 | TH120 | A | chloro | benzo[b]thien-7-yl | 97 ± 16 | 7.01 | 6.81 | 0.20 | −0.24 | −8.90 |
7 | TH125 | A | methoxy | 1H-benzo[d]imidazol-2-yl | 575 ±72 | 6.24 | 6.86 | −0.62 | −0.29 | −9.48 |
8 | TH127 | A | methoxy | 3-benzyloxyphenyl | 605 ± 68 | 6.22 | 6.66 | −0.44 | −0.09 | −9.23 |
9 | TH128 | A | methyl | 3-benzyloxyphenyl | 447 ± 31 | 6.35 | 6.43 | −0.08 | 0.14 | −8.63 |
10 | TH132 | A | methoxy | 2-chloro-4-biphenyl | 101 ± 77 | 7.00 | 6.68 | 0.31 | −0.11 | −8.71 |
11 | TH133 | A | chloro | 2-chloro-4-biphenyl | 112 ± 11 | 6.95 | 6.77 | 0.18 | −0.20 | −8.35 |
12 | TH134 | A | methoxy | 4-propoxyphenyl | 729 ± 86 | 6.14 | 6.19 | −0.05 | 0.38 | −8.51 |
13 | TH135 | A | methoxy | 4-isopropoxyphenyl | 725 ± 52 | 6.14 | 6.86 | −0.72 | −0.29 | −8.76 |
14 | TH136 | A | methoxy | 2,4-dimethoxyphenyl | 2078 ± 273 | 5.68 | 6.90 | −1.22 | −0.33 | −9.29 |
15 | TH137 | A | chloro | 2,4-dimethoxyphenyl | 220 ± 13 | 6.66 | 6.51 | 0.15 | 0.06 | −9.22 |
16 | TH138 | A | methoxy | 2-chloro-4-(4-fluorophenyl)phenyl | 318 ± 19 | 6.50 | 6.37 | 0.13 | 0.20 | −8.99 |
17 | TH139 | A | chloro | 2-chloro-4-(4-fluorophenyl)phenyl | 281 ± 37 | 6.55 | 6.70 | −0.14 | −0.13 | −8.66 |
18 | TH142 | A | methoxy | quinolin-8-yl | 332 ± 51 | 6.48 | 6.98 | −0.50 | −0.41 | −9.84 |
19 | TH143 | A | methoxy | 4-dibenzofuranyl | 271 ± 30 | 6.57 | 6.91 | −0.34 | −0.34 | −9.76 |
20 | TH156 | B | methoxy | 4-dibenzofuranyl | 451 ± 90 | 6.35 | 5.98 | 0.37 | 0.59 | −9.42 |
21 | TH34 | B | methyl | benzyl | 1260 ± 170 | 5.90 | 6.18 | −0.28 | 0.39 | −9.15 |
22 | TH42 | B | methoxy | benzyl | 620 ± 0 | 6.21 | 6.13 | 0.08 | 0.44 | −9.74 |
23 | TH97 | - | - | - | 220 ± 67 | 6.66 | 6.77 | −0.11 | −0.26 | −8.13 |
24 | TH98 | - | - | - | 1590 ± 190 | 5.80 | 6.49 | −0.69 | 0.08 | −9.59 |
Notation | Molecular Descriptors |
---|---|
a_heavy | Number of heavy atoms |
b_1rotN | Number of rotatable single bonds. Conjugated single bonds are not included |
b_single | Number of single bonds (including implicit hydrogens). Aromatic bonds are not considered to be single bonds. |
lip_acc | The number of O and N atoms. |
lip_don | The number of OH and NH atoms. |
mr | Molecular refractivity (including implicit hydrogens). |
PEOE_VSA_POL | The number of OH and NH atoms. |
TPSA | Polar surface area (Å2) calculated using group contributions to approximate the polar surface area from connection table information only. |
h_logD | The octanol/water distribution coefficient at pH 7. |
PEOE_VSA_FPPOS * | Fractional positive polar van der Waals surface area. |
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Simoben, C.V.; Ghazy, E.; Zeyen, P.; Darwish, S.; Schmidt, M.; Romier, C.; Robaa, D.; Sippl, W. Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors. Molecules 2021, 26, 2584. https://doi.org/10.3390/molecules26092584
Simoben CV, Ghazy E, Zeyen P, Darwish S, Schmidt M, Romier C, Robaa D, Sippl W. Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors. Molecules. 2021; 26(9):2584. https://doi.org/10.3390/molecules26092584
Chicago/Turabian StyleSimoben, Conrad V., Ehab Ghazy, Patrik Zeyen, Salma Darwish, Matthias Schmidt, Christophe Romier, Dina Robaa, and Wolfgang Sippl. 2021. "Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors" Molecules 26, no. 9: 2584. https://doi.org/10.3390/molecules26092584