Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches
Abstract
:1. Introduction
2. Results
2.1. Generation of C1s Inhibitor Focused Library (by 2D Methods)
2.2. Generation of C1s Inhibitor Focused Library (Pharmacophore Search Methods)
2.3. Generation of C1s Inhibitor Hit-Validation Small Library
2.4. In Vitro Screening Results
2.4.1. C1s Inhibition
2.4.2. Factor Xa Inhibition
3. Discussion
3.1. Structure–Activity Relationship of the Chemotypes
3.1.1. 1,2,3-Benzotriazoles
- (1)
- A substituted benzoyl group in the N-1 position is required for the activity. Unsubstituted benzoyl groups or replacement with an N-1 furoyl group is detrimental to the activity.
- (2)
- The position and nature of the functional groups on the benzoyl group have a significant impact on the activity. The para position is much favored, followed by the ortho position. Substituents in the meta position generally diminish or occasionally fully eliminate the activity. However, meta/para disubstitution somewhat counterbalances this negative effect.
- (3)
- Electron donating groups (amide, ether, thioether) at the para position are particularly beneficial. Alkyl groups are weaker in the para position, but interestingly bulky alkyl groups (t-butyl) look better. Interestingly, while a meta/para difluoro-substituted compound is relatively good inhibitor, analogous dichloro substitution and para-bromo substitution led to inactive compounds. Electron acceptor groups in the para position (such as nitro group) eliminate the activity.
3.1.2. 1,2,4-Triazoles
- (1)
- Unsubstituted aroyl (furan-carbonyl, thiophene-carbonyl and benzoyl) groups in the N-1 position are beneficial. Ortho and para substitutions of the N-1 benzoyl group (such as methyl, methoxy, and fluoro) have also positive contributions. Replacing the N-1 aroyl groups to propionyl, benzyl-carbonyl leads to the loss of the activity.
- (2)
- Replacing the methyl-thio group to primary/secondary amines or bulky aralkyl groups results in inactive compounds.
- (3)
- Changing the C-3 furyl group to thiophenyl (PubChem, CID 4257399; IC50 = 880 nM) or 3-pyridyl group (#12; IC50 = 2.4 μM) retains the activity, while replacing with para-chloro-phenyl leads to inactivation.
3.1.3. 3,1-Benzoxazin-4-ones
- (1)
- Halogen (chloro) in the C-7 position is much favored over the C-6 position as well as to the unsubstituted 2-aryl-3,1-benzoxazin-4-ones.
- (2)
- Replacing the furyl group to 2′-iodo-phenyl at the C-2 position improves the activity, while 4′-fluorophenyl group in the same position eliminates the activity.
- (3)
- If the furyl group at the C-2 position replaced with a bulky 2-benzofuryl group the compound loses the activity.
3.1.4. 1,3-Benzoxazin-4-ones
- (1)
- Since thiophene and furan are interchangeable in many bioactive compounds, therefore, the trend of the decreasing activity between #21 and #22 is comparable to the same direction between #13 and #15, thus, halogen (chloro) in the C-7 position is much favored over the C-6 position.
- (2)
- Introducing 4′-chlorophenyl group or alkyl groups at the C-2 position instead of furyl or thiophenyl groups leads to inactivation.
- (3)
- Finally, if N-3 is replaced with carbon forming the corresponding chromen-4-one, it results in a complete loss of the activity.
3.1.5. Thieno[2,3-d][1,3]oxazin-4-ones
- (1)
- Similarly to 3,1-benzoxazin-4-ones replacing the furyl group with 2′-halogeno (bromo)-phenyl at the C-2 position retains the activity, while unsubstituted phenyl, 4′-tolyl, 4′-halogeno (fluoro, chloro) substituted phenyl groups in the same position significantly reduce or completely eliminate the activity.
- (2)
- Introducing a bulky (thiophenyl) group into the thiophenyl part of the fused ring leads to complete inactivation.
3.1.6. Structural Features of the C1s Selectivity over Factor Xa
4. Materials and Methods
4.1. Molecular Biology. Protein Expression of C1s
4.2. Assay Development
4.3. Factor Xa (FXa) Assay Development
4.4. Chemoinformatics Methods
4.4.1. 2D Similarity Selection
4.4.2. 3D Modelling
X-Ray Structures
Ligand Preparation
Protein Preparation and Docking
4.4.3. Pharmacophore Modeling
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Entry | Structure | IDNUMBER | IC50 C1s; µM | LogP | TPSA | H Bond Acceptors | H Bond Donors | Rotatable Bonds | Lipinski Rule of 5 (4 of 4) | Chemoinformatics |
---|---|---|---|---|---|---|---|---|---|---|
1 | BAS 00784557 | 0.083 | 2.6744 | 57.01 | 4 | 0 | 3 | true | 2D similarity | |
2 | 2616-0473 | 0.091 | 1.713 | 76.88 | 4 | 1 | 2 | true | 2D similarity | |
3 | 3502-2773 | 0.24 | 2.9458 | 57.01 | 4 | 0 | 3 | true | Pharmacophore | |
4 | 8008-1157 | 1.30 | 4.0203 | 47.78 | 3 | 0 | 2 | true | 2D similarity | |
5 | 4130-3864 (CHEMBL-143333)7 | 1.85 | 2.1599 | 66.24 | 5 | 0 | 3 | true | 2D similarity | |
6 | 8012-0883 | 2.16 | 2.7607 | 47.78 | 3 | 0 | 1 | true | Pharmacophore | |
7 | BAS 00785517 | 3.867 | 4.1225 | 47.78 | 3 | 0 | 2 | true | 2D similarity | |
8 | 3455-3034 | 5.90 | 3.2969 | 51.02 | 4 | 0 | 4 | true | 2D similarity |
Entry | Structure | IDNUMBER | IC50 C1s; µM | LogP | TPSA | H Bond Acceptors | H Bond Donors | Rotatable Bonds | Lipinski rule of 5 (4 of 4) | Chemoinformatics |
---|---|---|---|---|---|---|---|---|---|---|
9 | BAS 07161957 (CHEMBL-490106) | 0.012 | 3.45 | 70.15 | 4 | 0 | 4 | true | 2D similarity | |
10 | BAS 07161950 | 0.044 | 3.79 | 60.92 | 3 | 0 | 3 | true | 2D similarity | |
11 | BAS 07161949 (CHEMBL-490107) | 0.094 | 3.65 | 60.92 | 3 | 0 | 3 | true | 2D similarity | |
12 | ASN 01365717 | 2.4 | 2.97 | 86.97 | 5 | 0 | 7 | true | 2D similarity |
Entry | Structure | IDNUMBER | IC50 C1s; µM | LogP | TPSA | H Bond Acceptors | H Bond Donors | Rotatable Bonds | Lipinski Rule of 5 (4 of 4) | Chemoinformatics |
---|---|---|---|---|---|---|---|---|---|---|
13 | 3226-0357 | 0.474 | 3.02 | 51.80 | 2 | 0 | 1 | true | Pharmacophore | |
14 | Z55930777 | 6.44 | 2.10 | 70.26 | 4 | 0 | 3 | true | Pharmacophore | |
15 | BAS 01170083 | 6.7 | 3.02 | 51.80 | 2 | 0 | 1 | true | 2D similarity | |
16 | 4334-1472 (CHEMBL-1449374 | 29 | 2.02 | 78.10 | 3 | 0 | 3 | true | 2D similarity |
Entry | Structure | IDNUMBER | IC50 C1s; µM | LogP | TPSA | H Bond Acceptors | H Bond Donors | Rotatable Bonds | Lipinski Rule of 5 (4 of 4) | Chemoinformatics |
---|---|---|---|---|---|---|---|---|---|---|
17 | STOCK1S-76323 (CHEMBL-1333976) | 0.549 | 3.52 | 51.80 | 2 | 0 | 1 | true | Pharmacophore | |
18 | STOCK3S-12710 (CHEMBL-1501165) | 0.845 | 4.72 | 38.66 | 2 | 0 | 1 | true | Hit validation | |
19 | STOCK2S-97295 (CHEMBL-1441606) | ~20 | 4.46 | 38.66 | 2 | 0 | 1 | true | Hit validation | |
20 | STOCK2S-12571 | ~50 | 4.98 | 38.66 | 2 | 0 | 1 | true | Hit validation |
Entry | Structure | IDNUMBER | IC50 C1s; µM | LogP | TPSA | H Bond Acceptors | H Bond Donors | Rotatable Bonds | Lipinski Rule of 5 (4 of 4) | Chemoinformatics |
---|---|---|---|---|---|---|---|---|---|---|
21 | Z55992821 | 0.241 | 3.20 | 38.66 | 2 | 0 | 1 | true | Pharmacophore | |
22 | Z55992803 | 3.6 | 2.35 | 51.80 | 2 | 0 | 1 | true | Hit validation | |
23 | Z55992807 | 41 | 2.26 | 51.80 | 2 | 0 | 1 | true | Hit validation |
Entry | Factor Xa 10 µM Remaining Activity % | Entry | Factor Xa 10 µM Remaining Activity % |
---|---|---|---|
1 | 30.3 | 11 | 26.02 |
2 | 43.1 | 12 | 85.4 |
3 | 4.93 | 13 | 98.6 |
4 | 86.2 | 14 | 61.4 |
5 | 48.3 | 15 | 82 |
6 | 92.3 | 16 | 77.6 |
7 | 92.1 | 17 | 100 |
8 | 76.5 | 18 | 46.1 |
9 | 2.39 | 21 | 53.6 |
10 | 78.1 | 22 | 0.14 |
Entry | IC50 (µM) | Glide Docking Score | Glide Emodel Score |
---|---|---|---|
1 | 0.083 | −6.404 | −58.321 |
2 | 0.091 | −6.866 | −65.171 |
4 | 1.300 | −7.003 | −60.058 |
5 | 1.850 | −6.791 | −59.201 |
7 | 3.870 | −7.558 | −65.852 |
9 | 0.012 | −6.592 | −62.262 |
10 | 0.044 | −6.099 | −54.519 |
11 | 0.094 | −6.993 | −60.231 |
Compound ID | IC50 (µM) | Glide Docking Score | Glide Emodel Scores |
---|---|---|---|
17178137 | 11.0 | −5.538 | −53.585 |
4951143 | 19.1 | −5.595 | −57.808 |
2986934 | 0.34 | −6.892 | −67.866 |
710644 | 1.09 | −6.556 | −55.670 |
5146207 | >50 | −6.495 | −54.781 |
807111 | >50 | −5.909 | −58.543 |
1107361 | >50 | −6.621 | −67.010 |
827004 | 3.04 | −7.022 | −55.173 |
4957387 | 32.9 | −6.737 | −60.524 |
898930 | 5.54 | −6.733 | −57.680 |
Pharmacophore Model | PhaseHypo-Score | Survival Score | Selectivity Score | BEDROC160.9 (from Validation) | ROC | EF1% |
---|---|---|---|---|---|---|
ARRR_1 | 1.319 | 5.317 | 1.219 | 0.67 | 0.63 | 2.78 |
ARRR_2 | 1.318 | 5.305 | 1.211 | 0.74 | 0.51 | 2.78 |
AARR_1 | 1.315 | 5.247 | 1.150 | 0.67 | 0.79 | 2.78 |
AARR_2 | 1.314 | 5.236 | 1.139 | 0.67 | 0.80 | 2.78 |
AARR_3 * | 1.314 | 5.231 | 1.141 | 0.92 | 0.81 | 5.56 |
Pharmacophore Model | PhaseHypoScore | Survival Score | Selectivity Score | BEDROC160.9 (from Validation) | ROC Score | EF1% |
---|---|---|---|---|---|---|
AHRR_1 * | 1.283 | 5.175 | 1.358 | 0.52 | 0.40 | 2.78 |
AAAHRR_1 | 1.259 | 5.833 | 2.034 | 0.29 | 0.09 | 2.78 |
AAAHRR_2 | 1.258 | 5.828 | 2.026 | 0.14 | 0.11 | 0.00 |
AAAHRR_3 | 1.258 | 5.826 | 2.029 | 0.11 | 0.11 | 0.00 |
AHRRR_1 | 1.249 | 5.665 | 1.87 | 0.04 | 0.23 | 0.00 |
Pharmacophore Model | PhaseHypoScore | Survival Score | Selectivity Score | BEDROC160.9 (from validation) | ROC | EF1% |
---|---|---|---|---|---|---|
AAARR_1 | 1.288 | 4.808 | 1.373 | 0.86 | 0.62 | 5.56 |
ARRR_1 | 1.279 | 4.646 | 1.214 | 0.86 | 0.52 | 5.56 |
AARR_1 | 1.274 | 4.574 | 1.142 | 0.86 | 0.76 | 5.56 |
AARR_2 | 1.274 | 4.562 | 1.131 | 0.86 | 0.66 | 5.56 |
AARR_3 * | 1.273 | 4.550 | 1.118 | 0.86 | 0.84 | 5.56 |
Domains | Position | Length (aa) | X-Ray Structures | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
1ELV * | 1NZI | 4J1Y * | 4LMF | 4LOR | 4LOS | 4LOT | 6F1C | 6F1H | 5UBM * | |||
signal peptide | 1–15 | 15 | x | x | x | x | x | x | x | x | x | x |
CUB 1 | 16–130 | 115 | − | + | − | + | + | − | − | + | + | − |
EGF-like | 131–172 | 42 | − | + | − | + | + | − | − | + | + | − |
CUB 2 | 175–290 | 116 | − | − | − | + | + | + | + | + | + | − |
Sushi/CCP1 | 292–356 | 65 | − | − | + | − | - | + | + | − | − | + |
Sushi/CCP2 | 357–423 | 67 | + | − | + | − | − | - | + | − | − | + |
SP (peptidase) | 438–688 | 243 | + | − | + | − | − | − | − | − | − | + |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Szilágyi, K.; Hajdú, I.; Flachner, B.; Lőrincz, Z.; Balczer, J.; Gál, P.; Závodszky, P.; Pirli, C.; Balogh, B.; Mándity, I.M.; et al. Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches. Molecules 2019, 24, 3641. https://doi.org/10.3390/molecules24203641
Szilágyi K, Hajdú I, Flachner B, Lőrincz Z, Balczer J, Gál P, Závodszky P, Pirli C, Balogh B, Mándity IM, et al. Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches. Molecules. 2019; 24(20):3641. https://doi.org/10.3390/molecules24203641
Chicago/Turabian StyleSzilágyi, Katalin, István Hajdú, Beáta Flachner, Zsolt Lőrincz, Júlia Balczer, Péter Gál, Péter Závodszky, Chiara Pirli, Balázs Balogh, István M. Mándity, and et al. 2019. "Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches" Molecules 24, no. 20: 3641. https://doi.org/10.3390/molecules24203641