Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists
Abstract
:1. Introduction
2. Results
2.1. 2D-QSAR Model
2.1.1. Development of 2D-QSAR Model
- VE3sign_D/Dt: the logarithmic coefficient sum of the last eigenvector from the distance–detour matrix [43].
- SpMin2_Bh(s): the second-smallest eigenvalue of the Burden Matrix of the H-filled molecular graph weighted by intrinsic state [44].
2.1.2. Validation of 2D-QSAR Model
Internal Validation
External Validation
2.1.3. Applicability Domain
2.2. Pharmacophore Model
2.2.1. Development of Pharmacophore Models
2.2.2. Pharmacophore Validation
Cost Analysis Method
Test Set Analysis
Fischer Randomization
2.3. 3D-QSAR
2.3.1. Development of the 3D-QSAR Model
2.3.2. 3D-QSAR Model Validation
2.3.3. Analysis of 3D-QSAR Contour Maps
2.4. Design of New Compounds
2.5. Molecular Docking of the Newly Designed Compounds
2.6. In Silico Pharmacokinetics Predictions
2.7. Toxicity Risk Assessment Screening
2.8. Molecular Dynamics Simulation
3. Materials and Methods
3.1. Dataset Selection
3.2. 2D-QSAR
3.2.1. 2D-QSAR Model Generation
3.2.2. 2D-QSAR Model Validation
3.2.3. Interpretation of Descriptors of the Developed 2D-QSAR Model
- VE3sign_D/Dt, the first descriptor of the 2D-QSAR model equation, is expressed as a negative coefficient. It represents the logarithmic coefficient sum of the last eigenvector from the distance–detour matrix [43] and is expressed as the following equation:
- SpMin2_Bh(s) bears the largest coefficient value with a positive sign. It represents the second-smallest eigenvalue of the Burden Matrix of the H-filled molecular graph weighted by intrinsic state [43,81]. It is a square symmetric matrix expressed as:
- P_VSA_logP_5, the third parameter of the model, is a lipophilicity-based descriptor representing the P_VSA-like on LogP, bin 5, that is the sum of the Van der Waals surface area of atoms with logP values in the range of 0 to 0.25. This descriptor can also positively influence the activity, having a positively signed coefficient, and it is presented by both the size and hydrophobicity values of the atoms [45]. The Alvascience user manual [43] lists the individual octanol-water partition coefficient values of 115 atom-centered fragments, in which groups such as CR2X2, =CR2, =CX2, R:CR:R, R…O…R, and R-O-C=X specifically bear logP values ranging from 0 to 0.25 [83,84]. The atoms belonging to these and having larger atomic Van der Waals surface areas can be beneficially incorporated to enhance activity.
- Eig02_EA(dm), or the second eigenvalue from the edge adjacency matrix weighted by the dipole moment [43,46], is a negative contributor with a significant coefficient value, which emphasizes that adjacent bonds with large dipole moments are likely to decrease activity. It indicates that the substituent groups having greater charge distributions inflicted by electronegative atoms can have a negative influence if the involved bond is branched and connected to several other components in the H-depleted molecular connection map.
- CATS2D_09_AA is the number of hydrogen bond acceptors at an in-between topological distance of 9 bonds [43,47] and points out the frequency of such occurrences as a negative contributor to activity. Although the central core bears several nitrogen atoms that can be potential hydrogen bond acceptors, a topological distance of 9 bonds is not very frequent. However, as in the case of molecule 3, the symmetric pattern of the carbonyl oxygen atoms, piperazine ring, and fused pyrimidine contributed to the large value of this descriptor.
3.2.4. Applicability Domain
3.3. Pharmacophore Model Generation
3.3.1. Generation of Pharmacophore Hypothesis with 3D-QSAR Pharmacophore Generation (Hypogen)
3.3.2. Pharmacophore Validation
3.4. 3D-QSAR Model Generation
3.4.1. Molecular Alignment
3.4.2. 3D-QSAR Model Development and Validation
3.5. Molecular Docking
3.6. ADMET and Toxicity Prediction
3.7. MD Simulation
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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Hypo. No. | Total Cost | Cost Difference | RMSD | Correlation | Max. Fit | Features |
---|---|---|---|---|---|---|
1 | 141.90 | 89.77 | 0.87 | 0.94 | 5.40 | HBA, HYA, PI, RA |
2 | 146.16 | 85.50 | 0.99 | 0.92 | 5.29 | HBA, HBA, HYA, PI |
3 | 146.47 | 85.19 | 1.02 | 0.92 | 5.77 | HBA, HYA, PI, RA |
4 | 148.27 | 83.40 | 1.03 | 0.92 | 6.10 | HBA, HBA, HYA, PI, PI |
5 | 148.27 | 83.40 | 1.03 | 0.92 | 5.01 | HBA, HBA, HYA, PI |
6 | 149.04 | 82.63 | 0.99 | 0.92 | 4.00 | HYA, PI, PI, RA |
7 | 149.04 | 82.62 | 1.05 | 0.91 | 4.93 | HBA, HYA, PI, RA |
8 | 149.11 | 82.55 | 1.07 | 0.91 | 5.34 | HBA, HYA, PI, RA |
9 | 149.13 | 82.53 | 0.97 | 0.93 | 3.78 | HYA, PI, PI, RA |
10 | 149.48 | 82.19 | 1.03 | 0.92 | 5.55 | HBA, HBA, HYA, PI, PI |
Comp No. | IC50 (μM) | Errors a | Fit Value b | Activity Scale c | ||
---|---|---|---|---|---|---|
Experimental | Estimated | Experimental | Estimated | |||
32 | 0.43 | 0.63 | +1.47 | 5.06 | ++++ | ++++ |
33 | 0.5 | 0.75 | +1.5 | 4.98 | ++++ | ++++ |
14 | 0.7 | 1.7 | +2.43 | 4.64 | ++++ | ++++ |
38 | 0.8 | 0.73 | −1.1 | 5.00 | ++++ | ++++ |
36 | 0.98 | 0.91 | −1.08 | 4.92 | ++++ | ++++ |
35 | 0.99 | 0.73 | −1.36 | 4.99 | ++++ | ++++ |
37 | 1.14 | 0.84 | −1.36 | 4.95 | ++++ | ++++ |
19 | 1.2 | 3.1 | +2.58 | 4.37 | ++++ | +++ |
39 | 1.4 | 3.1 | +2.21 | 4.88 | ++++ | +++ |
13 | 1.4 | 1 | −1.4 | 4.37 | ++++ | ++++ |
34 | 1.55 | 0.99 | −1.57 | 4.88 | ++++ | ++++ |
15 | 4.4 | 8.3 | +1.89 | 3.95 | +++ | +++ |
53 | 4.57 | 5.8 | +1.27 | 4.11 | +++ | +++ |
48 | 4.71 | 5.4 | +1.15 | 4.12 | +++ | +++ |
24 | 4.9 | 5.6 | +1.14 | 4.13 | +++ | +++ |
50 | 4.99 | 5.7 | +1.14 | 4.10 | +++ | +++ |
17 | 5.4 | 7.3 | +1.35 | 4.01 | +++ | +++ |
22 | 5.7 | 8.1 | +1.42 | 3.96 | +++ | +++ |
12 | 5.8 | 2.7 | −2.15 | 4.44 | +++ | +++ |
52 | 8.09 | 7.8 | −1.04 | 3.98 | +++ | +++ |
HCQ | 8.2 | 17 | +2.07 | 3.62 | +++ | ++ |
49 | 8.3 | 11 | +1.33 | 3.83 | +++ | ++ |
21 | 8.7 | 4.1 | −2.12 | 4.25 | +++ | +++ |
18 | 9.6 | 6.9 | −1.39 | 4.03 | +++ | +++ |
16 | 11 | 8.6 | −1.28 | 3.94 | ++ | +++ |
26 | 16 | 8.1 | −1.98 | 3.97 | ++ | +++ |
27 | 17 | 7.6 | −2.24 | 3.99 | ++ | +++ |
25 | 17 | 7.5 | −2.27 | 3.97 | ++ | +++ |
7 | 20.7 | 37 | +1.79 | 3.30 | + | + |
5 | 22 | 9.1 | −2.42 | 3.91 | + | +++ |
4 | 31 | 31 | +1 | 3.36 | + | + |
45 | 37 | 160 | +4.32 | 2.67 | + | + |
1 | 53 | 37 | −1.43 | 3.30 | + | + |
41 | 185 | 190 | +1.03 | 2.60 | + | + |
42 | 253 | 530 | +2.09 | 2.15 | + | + |
43 | 272 | 160 | −1.7 | 2.66 | + | + |
44 | 684 | 180 | −3.8 | 2.62 | + | + |
Comp No. | IC50 (μM) | Errors a | Activity Scale b | ||
---|---|---|---|---|---|
Experimental | Estimated | Experimental | Estimated | ||
31 | 0.46 | 0.92 | +2.01 | ++++ | ++++ |
28 | 1.03 | 10.47 | +10.17 | ++++ | ++ |
23 | 1.2 | 4.27 | +3.55 | ++++ | +++ |
9 | 1.3 | 8.69 | +6.68 | ++++ | +++ |
2 | 1.4 | 8.69 | +6.21 | ++++ | +++ |
29 | 1.83 | 5.89 | +3.22 | ++++ | +++ |
30 | 2.16 | 7.59 | +3.63 | +++ | +++ |
20 | 4.2 | 6.17 | +1.47 | +++ | +++ |
6 | 4.6 | 8.71 | +1.89 | +++ | +++ |
11 | 5.6 | 6.61 | +1.18 | +++ | +++ |
51 | 7.55 | 5.62 | −1.34 | +++ | +++ |
10 | 11 | 39.81 | +3.62 | ++ | + |
8 | 17 | 38.90 | +2.29 | ++ | + |
40 | 23 | 157.04 | +6.83 | + | + |
3 | 52 | 36.31 | −1.43 | + | + |
47 | 110 | 190.55 | +1.73 | + | + |
| ||||||||
---|---|---|---|---|---|---|---|---|
Comp. | R1 | R2 | R3 | 2D-QSAR | 3D-QSAR | Pharmacophore | ||
pIC50 (µM) | IC50 (µM) | pIC50 (µM) | IC50 (µM) | IC50 (µM) | ||||
T55 | | | | −0.40 | 2.50 | −0.09 | 1.24 | 1.55 |
T56 | | | | −0.19 | 1.55 | −0.08 | 1.20 | 1.97 |
T57 | | | | −0.24 | 1.73 | 0.01 | 0.98 | 1.51 |
T58 | | | | −0.48 | 3.04 | −0.03 | 1.07 | 1.73 |
T59 | | | | 0.20 | 0.63 | −0.20 | 1.58 | 1.78 |
T60 | | | | 0.20 | 0.63 | −0.10 | 1.25 | 1.50 |
T61 | | | | 0.16 | 0.69 | 0.03 | 0.94 | 1.65 |
T62 | | | | 0.16 | 0.69 | −0.08 | 1.21 | 1.42 |
T63 | | | | −0.42 | 2.62 | 0.00 | 1.01 | 1.62 |
T64 | | | | 0.09 | 0.81 | −0.19 | 1.53 | 1.39 |
T65 | | | | −0.42 | 2.62 | −0.06 | 1.15 | 2.10 |
T66 | | | | −0.50 | 3.15 | 0.07 | 0.85 | 1.82 |
Comp. | Antagonist Structure | Interacting Residue | Hydrogen Bond Formed | H-Bond Distance (Å) | Docking Score (kcal/mol) |
---|---|---|---|---|---|
T55 | | Lys432*, Gln324, Gly577, Tyr356*, Ser523 | B:Lys432:HZ2–F38:T55 H44: T55O:Gln354:B T55:H60O:Gly577:A | 2.02 | 123.23 |
T56 | | Gln354*, Val355*, Gly577, Lys432* | B:Lys432:HZ2F38: T56 T56:H42O:Gln354:B T56:H42O:Val355:B T56:H58O:Gly577:A | 1.77 | 124.08 |
T57 | | Gln354*, Val355*, Gly577, Phe500 | T57:H43–O:Gln354:B T57:H43–O:Val355:B T57:H59–O:Gly577:A | 1.85 | 114.97 |
T58 | | Gln354*, Val355*, Gly577 | T58:H41–O:Gln354:B T58:H41–O:Val355:B T58:H57–O:Gly577:A | 1.81 | 110.54 |
T59 | | Thr525, Gln354*, Thr579, Tyr356* | T59:H42–OE1:Gln354:B T59:H42–O:Gln354:B T59:H58–OG1:Thr579:A T59:H77–OG1:Thr525:A | 1.81 | 115.88 |
T60 | | Gln354*, Thr525, Gly577 | T60:H42–O:Gln354:B T60:H63–OG1:Thr525:A T60:H89–O:Gly577:A | 2.53 | 133.30 |
T61 | | Gln354*, Thr525, Gly577, Tyr356* | T61:H41–O:Gln354:B T61:H62–OG1:Thr525:A T61:H87–O:Gly577:A | 1.74 | 111.78 |
T62 | | Gln354*, Gly577, Thr525, Asn255*, Tyr356* | T62:H41–B:Gln354:O T62:H57–A:Gly577:O T62:H62–A:Thr525:OG1 | 2.41 | 88.21 |
T63 | | Gln354*, Thr525, Gly577, Tyr356* | T63:H40–B:Gln354:O T63:H61–A:Thr525:OG1 T63:H85–A:Gly577:O | 2.16 | 108.50 |
T64 | | Gln354*, Thr525, Gly577, Tyr356* | T64:H40–O:Gln354:B T64:H56–O:Gly577:A T64:H61–OG1:Thr525:A | 2.98 | 110.24 |
T65 | | Gln354*, Thr525, Tyr356*, Thr406* | T65:H40–O:Gln354:B T65:H61–OG1:Thr525:A | 1.82 | 112.45 |
T66 | | Gln354*, Gly577, Thr525, Tyr356* | T66:H40–O:Gln354:B T66:H50–O:GLY577:A T66:H63–A:Thr525:OG1 | 2.47 | 116.22 |
Comp. | Absorption Level | AlogP98 | PSA | BBB | BBB Level | Solubility | Solubility Level | Hepato- Toxicity | CYP2D6 | CYP2D6 Probability |
---|---|---|---|---|---|---|---|---|---|---|
14 | 0 | 5.091 | 53.79 | 0.57 | 1.00 | −5.71 | 2 | False | −1.98 | False |
T55 | 1 | 5.861 | 53.79 | 0.81 | 0.00 | −6.00 | 1 | False | −0.78 | False |
T56 | 0 | 5.634 | 53.79 | 0.74 | 0.00 | −5.94 | 2 | False | −0.81 | False |
T57 | 0 | 5.303 | 62.72 | 0.49 | 1.00 | −5.49 | 2 | False | 0.52 | True |
T58 | 0 | 5.32 | 53.79 | 0.64 | 1.00 | −5.79 | 2 | False | 1.32 | True |
T59 | 1 | 6.256 | 53.79 | - | 4.00 | −6.31 | 1 | False | −3.40 | False |
T60 | 0 | 4.205 | 66.60 | 0.09 | 1.00 | −4.89 | 2 | False | −1.58 | False |
T61 | 0 | 4.063 | 74.61 | −0.08 | 2.00 | −4.45 | 2 | False | −2.75 | False |
T62 | 0 | 5.003 | 53.79 | 0.54 | 1.00 | −5.44 | 2 | False | −2.28 | False |
T63 | 0 | 3.711 | 80.33 | −0.28 | 2.00 | −5.18 | 2 | False | −2.64 | False |
T64 | 0 | 5.548 | 53.79 | 0.71 | 0.00 | −6.01 | 1 | False | −1.26 | False |
T65 | 0 | 4.941 | 53.79 | 0.52 | 1.00 | −5.51 | 2 | False | −2.91 | False |
T66 | 0 | 5.469 | 53.79 | 0.69 | 1.00 | −6.03 | 1 | False | −0.70 | False |
Molecule | Molecular Weight (g/mol) | LogP | H-Bond Donors | H-Bond Acceptors | Number of Rotatable Bond | Polar Surface Area |
---|---|---|---|---|---|---|
14 | 496.69 | 5.09 | 0 | 8 | 10 | 57.2 |
T55 | 568.70 | 5.86 | 0 | 8 | 10 | 57.2 |
T56 | 536.68 | 5.63 | 0 | 8 | 10 | 57.2 |
T57 | 548.72 | 5.30 | 0 | 9 | 11 | 66.43 |
T58 | 518.69 | 5.32 | 0 | 8 | 10 | 57.2 |
T59 | 538.77 | 6.26 | 0 | 8 | 11 | 57.2 |
T60 | 539.76 | 4.21 | 1 | 9 | 11 | 69.23 |
T61 | 526.71 | 4.06 | 1 | 9 | 10 | 77.43 |
T62 | 528.71 | 5.00 | 0 | 8 | 10 | 57.2 |
T63 | 511.70 | 3.71 | 1 | 9 | 10 | 83.22 |
T64 | 510.72 | 5.55 | 0 | 8 | 10 | 57.2 |
T65 | 514.68 | 4.94 | 0 | 8 | 10 | 57.2 |
T66 | 510.72 | 5.47 | 0 | 8 | 10 | 57.2 |
Comp. | FDA Carcinogenicity | FDA Carcinogenicity | AMES Mutagenicity | Rat oral LD50 (mg/kg) | Skin Irritation | Probability of Biodegradability | ||
---|---|---|---|---|---|---|---|---|
Male Mouse | Female Mouse | Male Rat | Female Rat | |||||
14 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 81.63 | None | Non- degradable |
T55 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 9.70 | None | Non- degradable |
T56 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 53.89 | None | Non- degradable |
T57 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 171.96 | None | Non- degradable |
T58 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 73.78 | None | Non- degradable |
T59 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 65.11 | Mild | Non- degradable |
T60 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 36.50 | Mild | Non- degradable |
T61 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 79.04 | Mild | Non- degradable |
T62 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 17.71 | Mild | Non- degradable |
T63 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 44.17 | Mild | Non- degradable |
T64 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 101.52 | None | Non- degradable |
T65 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 13.12 | Mild | Non- degradable |
T66 | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- carcinogen | Non- mutagen | 42.90 | None | Non- degradable |
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Pal, S.; Ghosh Dastidar, U.; Ghosh, T.; Ganguly, D.; Talukdar, A. Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists. Molecules 2022, 27, 4026. https://doi.org/10.3390/molecules27134026
Pal S, Ghosh Dastidar U, Ghosh T, Ganguly D, Talukdar A. Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists. Molecules. 2022; 27(13):4026. https://doi.org/10.3390/molecules27134026
Chicago/Turabian StylePal, Sourav, Uddipta Ghosh Dastidar, Trisha Ghosh, Dipyaman Ganguly, and Arindam Talukdar. 2022. "Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists" Molecules 27, no. 13: 4026. https://doi.org/10.3390/molecules27134026