Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40
Abstract
:1. Introduction
2. Results
2.1. Binding Site Analysis
2.2. In Silico Screening
2.3. Prediction of Pharmacokinetic Properties and Toxicity Assessment
2.4. Molecular Interaction with EBOV-Z VP35 and VP40
2.5. Alignments and Structural Studies
2.6. Retrospective Evaluation Virtual Screening Method
2.7. Aggregator Advisor Screening
2.8. Metabolic Sites Analysis
3. Discussion
4. Materials and Methods
4.1. Dataset Preparation and Filtering Procedure
4.2. Evaluation of Protein Binding Site
4.3. Alignments and Homology Modelling
4.4. Structure-Based Virtual Screening
4.5. Retrospective Virtual Screening Analysis
4.6. Calculations of Pharmacokinetics and Toxicity Analysis
4.7. Aggregator Advisor Prediction
4.8. Metabolic Site Prediction
5. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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ADMET | Compd. 1 | Compd. 2 | Compd. 3 | Compd. 4 | Compd. 5 | Compd. 6 | Compd. 7 | Compd. 8 | Compd. 9 | Compd. 10 | Compd. 11 | Compd. 12 | Compd. 13 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
BBB | + | + | + | + | + | + | + | + | + | + | + | + | + |
HIA | + | + | + | + | + | + | + | + | + | + | + | + | + |
Caco-2 permeable | − | _ | − | − | + | + | − | − | + | + | + | − | − |
Solubility | −3.16 | −3.1 | −3.25 | −3.25 | −5.24 | −4.33 | −4.38 | −2.44 | −2.53 | −2.89 | −2.62 | −3.63 | −2.53 |
P-gp | |||||||||||||
Substrate | + | − | − | + | + | − | + | − | − | − | + | − | − |
Inhibitor | − | − | − | − | + | − | + | − | − | − | − | − | − |
ROCT | − | − | − | − | − | − | − | − | − | + | − | − | |
CYP450 substrate | |||||||||||||
2C9 | − | − | − | − | − | − | − | − | − | − | − | − | − |
2D6 | − | − | − | − | − | − | − | − | − | − | + | − | − |
3A4 | − | − | − | − | + | − | − | − | − | + | + | + | |
CYP450 inhibitor | |||||||||||||
1A2 | + | + | + | + | + | − | − | − | − | − | − | − | |
2C9 | − | − | − | − | + | − | − | − | − | − | − | − | − |
2D6 | − | − | − | − | − | − | − | − | − | − | − | − | − |
2C19 | + | − | − | − | + | − | − | − | − | − | − | − | − |
3A4 | − | − | + | − | + | − | − | − | − | − | + | − | − |
CYP IP | Low | Low | Low | Low | Low | Low | Low | Low | Low | Low | Low | Low | Low |
AMES toxicity | − | − | − | − | − | − | − | − | − | − | − | − | − |
Carcinogens | − | − | − | − | − | − | − | − | − | − | − | − | − |
Virtual Hits | Oral Bioavailability | ADMET | Drug Safety Profiling | Filtered State | Undesirable Structuresmioties | Aggregator Advisor | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Drug Likeness | Lipinski’s Ro5 | Veber Rule | Egan Rule | GSK 4/400 Rule | Pfizer 3/75 Rule | Lilly MedChem Rules | Aggregator Likelihood | Similar with | |||||
1 | √ | √ | √ | √ | √ | √ | × | √ | Rejected | High_risk coumarines | Reported as an aggregator | | |
Logp: 1.6 | Tc: 97% | ||||||||||||
2 | √ | √ | √ | √ | √ | √ | √ | √ | Intermediate | Low_risk coumarines | Non-aggregator Logp: 2.0 | ||
3 | √ | √ | √ | √ | √ | √ | × | √ | Rejected | High_risk coumarines | Reported as an aggregator | | |
Logp: 2.0 | Tc: 93% | ||||||||||||
4 | √ | √ | √ | √ | √ | √ | √ | × | Intermediate | Low_risk coumarines | Reported as an aggregator | | |
Logp: 3.2 | Tc: 76% | ||||||||||||
5 | √ | √ | √ | √ | √ | √ | × | √ | Intermediate | Low_risk coumarines | Not similar to any known aggregator in in-house database High Logp: 5.2 | ||
6 | √ | √ | √ | √ | √ | √ | × | × | Intermediate | Low_risk coumarines | Reported as an aggregator | | |
Logp: 4.0 | Tc: 75% | ||||||||||||
7 | √ | √ | √ | √ | √ | √ | √ | × | Rejected | High_risk epoxide | Non-aggregator Logp: 2.8 | ||
8 | √ | √ | √ | √ | √ | √ | √ | √ | Accepted | No | Non-aggregator Logp: 0.4 | ||
9 | √ | √ | √ | √ | √ | √ | √ | √ | Accepted | No | Non-aggregator Logp: 2.6 | ||
10 | √ | √ | √ | √ | √ | √ | √ | √ | Accepted | No | Non-aggregator Logp: 1.1 | ||
11 | √ | √ | √ | √ | √ | √ | × | √ | Rejected | Frequent_hitter dopamine; Low_risk benzodioxolane | Non-aggregator Logp: 2.3 | ||
12 | √ | √ | √ | √ | √ | √ | √ | √ | Accepted | No | Non-aggregator Logp: 2.8 | ||
13 | √ | √ | √ | √ | √ | √ | √ | √ | Accepted | No | Reported as an aggregator | | |
Logp: 0.2 | Tc: 90% |
Source-ID/Name/Formula | Autodock Vina (ΔG) | DSX Drugscore | Molecular Interactions | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
EBOV-Z VP35 (kcal/mol) | EBOV-Z VP40 (kcal/mol) | EBOV-Z VP35 | EBOV-Z VP40 | EBOV-Z VP35 | EBOV-Z VP40 | ||||||||||
Score (kcal/mol) | PCS | Score (kcal/mol) | PCS | Binding Site Interacting Residues | No. of H-Bond Interactions | No. of Hydrophobic Bonds Interactions | Total Number of Bonds | Binding Site Interacting Residues | No. of H-Bond Interactions | No. of Hydrophobic Bonds Interactions | Total number of Bonds | ||||
1 | Timtec-ST45161107 2-Oxo-N-(2-{4-((2-oxo-2H-chromen-3-yl)carbonyl)-1-piperazinyl}ethyl)-2H-chromene-3-carboxamide C26H23N3O6 | −9.2 | −7.1 | −156.867 | −0.265 | −120.189 | −0.255 | Lys248, Pro293, Ile295, Val245, Phe328, Ile297, Asp302, Pro304, Gln244, Tyr229, Gly236, His240, Gln241, Phe235 | 0 | 31 | 31 | Gly126, Thr123, His124, Thr173, Phe174, Ile82, Phe172, Tyr171, Phe125, Gly126 | 0 | 30 | 30 |
2 | Otava-7118230235 2-Oxo-N-((4-oxo-3,4-dihydro-1-phthalazinyl)methyl)-2H-chromene-3-carboxamide C19H13N3O4 | −8.6 | −6.9 | −133.08 | −0.291 | −95.698 | −0.229 | Ile303, Pro304, Asp302, Gln244, Val245, Gln241, Phe328, Ile297, Lys248, Pro293, Ile295 | 0 | 27 | 27 | His124, Phe125, Thr123, Tyr171, Thr173, Phe174, Ile82, Phe172 | 1 (3.18A) Thr173 | 30 | 31 |
3 | Timtec-ST50912611 N,N'-1,2-Ethanediylbis (2-oxo-2H-chromene-3-carboxamide) C22H16N2O6 | −8.2 | −7.2 | −152.793 | −0.317 | −115.494 | −0.247 | Val245, Pro293, Ile303, Ile295, Lys248, Gln241, Pro304, Gln244, Asp302, Phe328, Ile297 | 1 (3.12) His296 | 28 | 29 | Phe174, Ile82, Thr173, His124, Thr123, Phe125, Arg134, Tyr171, Phe172 | 0 | 29 | 29 |
4 | Timtec-ST50616170 N-(4-Methyl-2-oxo-2H-chromen-7-yl)-4,5,6,7-tetrahydro-1,2-benzoxazole-3-carboxamide C18H16N2O4 | −8.3 | −6.4 | −111.212 | −0.24 | −93.831 | −0.203 | Val245, Pro293, Ile303, Ile295, Lys248, Gln241, Pro304, Gln244, Asp302, Phe328, Ile297, Val294 | 0 | 29 | 29 | Phe174, Thr173, His124, Thr123, Phe125, Tyr171, Phe172 | 1 (3.12A) Thr173 | 28 | 29 |
5 | Analyticon-NP-010155 7-{((1R,4aS,6R,8aR)-6-hydroxy-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)methoxy}-2H-chromen-2-one C24H30O4 | −8 | −6.3 | −105.282 | −0.25 | −98.943 | −0.232 | Val294, Ile295, Pro304, Gln241, Gln244, Lys248, Val245, Ala221, Lys251, Pro293 | 0 | 26 | 26 | Thr123, Thr173, Phe125, His124, Gln170, Gly126, Tyr171 | 1 (2.85A) Thr173 | 23 | 24 |
6 | Otava-0115540195 N-(1-Naphthyl)-2-oxo-2H-chromene-3-carboxamide C20H13NO3 | −8 | −6.9 | −124.21 | −0.269 | −91.619 | −0.283 | Ile295, Ile297, Asp302, Phe328, Phe235, Tyr229, Gly236, Pro304, His240, Gln241, Pro293, Val294, Lys248, Val245, Gln244 | 1 (3.11) Gln241 | 28 | 28 | Phe125, Arg134, His124, Thr123, Phe172, Thr173, Tyr171 | 0 | 20 | 20 |
7 | Analyticon-NP-019744 Kihadarnin A C26H30O9 | −7.8 | −7.3 | −102.276 | −0.198 | −91.924 | −0.213 | Gln244, Lys248, Ile295, Pro293, Leu249, Val294, Val245, His296 | 1 (2.93) His296 | 34 | 34 | Phe125, Arg134, His124, Thr123, Phe172, Tyr171 | 1 (3.27) Arg134 1 (3.13) Phe172 | 21 | 23 |
8 | Analyticon-NP-005474 2-(4-Hydroxyphenyl)-4-oxo-3,4-dihydro-2H-chromen-7-yl β-d-glucopyranoside C21H22O9 | −7.7 | −7 | −123.944 | −0.253 | −116.708 | −0.23 | Val245, Lys248, Gln244, Ile295, Pro293, Val294, His296 | 3 (3.11A, 3.12, 3.22A) His296 | 26 | 29 | Phe172, Thr123, His124, Gln170, Gly126, Phe125, Tyr171, Thr173 | 2 (3.01A, 3.03A) Thr173 2 (3.19A, 2.70A) Phe172 1 (2.97A) Thr123 1 (3.16A) His124 | 33 | 39 |
9 | PubChem-CID17597017 6,8-Dimethyl-2-((8-methyl-1-oxa-4,8-diazaspiro(4.5)dec-4-yl) carbonyl)-4H-chromen-4-one C20H24N2O4 | −7.6 | −6.7 | −98.897 | −0.258 | −91.398 | −0.213 | Pro293, Ile295, Phe328, Pro304, Gln244, Val245, Lys248, Val294 | 0 | 19 | 19 | Phe172, Thr123, Phe125, Tyr171, Thr173 | 0 | 19 | 19 |
10 | Analyticon-NP-000375 Lactupicrin C23H22O7 | −7.3 | −7.5 | −95.53 | −0.214 | −116.548 | −0.217 | Val 294, Pro 293, Gln244, Lys248, Val245, Ile295, Val294 | 1 (3.27) His296 | 29 | 30 | Phe172, Thr123, His124, Gln170, Gly126, Phe125, Tyr171 | 1 (3.10) Thr123 1 (3.24) Phe172 | 33 | 35 |
11 | Analyticon_NP-014205 Parfumine C20H19NO5 | −7.3 | −6.9 | −111.517 | −0.281 | −95.502 | −0.246 | Phe328, Val294, Gln244, Val245, Lys248, Ile295, Pro293 | 0 | 24 | 24 | Phe172, Thr123, His124, Phe174, Tyr171, Thr173 | 1 (3.00) Thr123 1 (3.21) Phe172 | 21 | 23 |
12 | Analyticon-NP-014522 (2R,2′R,4a′S,6′S,7′R,8a′S)-4,6′,7′-Trihydroxy-2′,5′,5′,8a′-tetramethyl-3′,4′,4a′,5′,6′,7,7′,8,8′,8a′-decahydro- 2′H-spiro(furo(2,3-e)isoindole-2,1′-naphthalen)-6(3H)-one C23H31NO5 | −7.2 | −6.9 | −97.222 | −0.227 | −96.182 | −0.243 | Phe328, Val245, Val294, Gln244, Val245, Lys248, Ile295, Pro293 | 0 | 26 | 26 | Phe172, His124, Thr123, Asn136, Arg134, Tyr171, Thr173 | 1 (2.89A) Thr173 1 (3.08A) Phe172 1 (3.29A) His124 1 (3.11A) Thr123 1 (3.12A) Asn136 | 21 | 26 |
13 | Analyticon_NP-003228 Isorutarin C20H24O10 | −7 | −6.4 | −105.752 | −0.238 | −91.824 | −0.194 | Val245, Asp302, Ile297, Gln241, Val294, Gln244, Val245, Lys248, Ile295, Pro293 | 1 | 19 | 19 | Ile82, Phe172, His124, Tyr171, Phe125, Thr123, Thr173, | 1 (2.96A) Tyr171 1 (3.13A) Thr123 | 19 | 19 |
Target Proteins | Ebola Strains | Template PDB ID | Query Cover | E-Value | Maximum Identity |
---|---|---|---|---|---|
VP40 | EBOV-T | 3TCQ.A | 100% | 0 | 76% |
EBOV-R | 3TCQ.A | 98% | 0 | 79% | |
EBOV-B | 3TCQ.A | 86% | 0 | 88% | |
VP35 | EBOV-S | 3KS4.A | 51% | 6.00 × 10−105 | 81% |
EBOV-T | 3KS4.A | 49% | 3.00× 10−102 | 82% | |
EBOV-B | 3KS4.A | 49% | 2.00× 10−100 | 80% |
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Mirza, M.U.; Ikram, N. Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40. Int. J. Mol. Sci. 2016, 17, 1748. https://doi.org/10.3390/ijms17111748
Mirza MU, Ikram N. Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40. International Journal of Molecular Sciences. 2016; 17(11):1748. https://doi.org/10.3390/ijms17111748
Chicago/Turabian StyleMirza, Muhammad Usman, and Nazia Ikram. 2016. "Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40" International Journal of Molecular Sciences 17, no. 11: 1748. https://doi.org/10.3390/ijms17111748