In Silico Studies Reveal Peramivir and Zanamivir as an Optimal Drug Treatment Even If H7N9 Avian Type Influenza Virus Acquires Further Resistance
Abstract
:1. Introduction
2. Results
2.1. Validation of Docking
2.2. Evaluation of The Best Drug Candidates against Wild Type As Well As Mutated N9
2.3. Binding Assessment of Potent Drugs with H7N9 Single, Double and Triple Mutants
2.4. Influence of Mutations on Drug Fitness to the Binding Pocket of NAs
2.5. Identification of the Best Fitting Drug to the Pocket
2.6. Predicted Pharmacokinetic Properties for the Drugs
3. Discussion
4. Main Limitations and Future Perspectives
5. Conclusions
6. Computational Methods
6.1. Structure Derivation and Preparation
6.2. Molecular Docking
6.3. Prediction of Pharmacokinetic Properties
6.4. PDB Files for the N9-Drug Complexes Obtained from Molecular Docking
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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R294 (4MWQ) | R294K (4MWW) | R119K | R372K | R294_119K | R294_372K | R119_372K | R294_119_372K | |
---|---|---|---|---|---|---|---|---|
Oselt. | −8.3 | −7.1 | −7.0 | −7.1 | −6.2 | −6.9 | −6.4 | −6.2 |
Zan. | −7.4 | −7.4 | −6.7 | −6.6 | −5.2 | −6.4 | −6.3 | −5.2 |
Per. | −8.7 | −8.0 | −7.2 | −7.4 | −6.3 | −6.2 | −6.6 | −6.0 |
Lan. | −7.7 | −8.1 | −6.7 | −7.1 | −5.0 | −5.3 | −6.5 | −5.2 |
L-Arg. | −8.0 | −7.1 | −6.5 | −6.4 | −5.8 | −6.4 | −6.6 | −6.3 |
Bens. | −7.1 | −6.6 | −6.3 | −5.2 | −6.5 | −6.2 | −6.0 | −6.6 |
R294 (4MWQ) | R294K (4MWW) | R119K | R372K | R294_119K | R294_372K | R119_372K | R294_119_372K | |
---|---|---|---|---|---|---|---|---|
Oselt. | 72.4 | 56.9 | 52.0 | 43.8 | 44.1 | 45.2 | 53.6 | 47.1 |
Zan. | 89.3 | 75.2 | 51.7 | 52.1 | 53.2 | 60.4 | 52.3 | 45.0 |
Per. | 93.9 | 79.0 | 60.0 | 50.0 | 53.2 | 49.1 | 58.3 | 46.8 |
Lan. | 86.9 | 77.1 | 54.9 | 51.3 | 46.7 | 55.5 | 57.1 | 47.9 |
L-Arg. | 46.8 | 45.3 | 41.5 | 34.8 | 41.0 | 41.5 | 42.0 | 40.0 |
Bens. | 57.8 | 53.3 | 49.0 | 48.1 | 51.8 | 49.8 | 56.9 | 55.5 |
R294 (4MWQ) | R294K (4MWW) | R119K | R372K | R294_119K | R294_372K | R119_372K | R294_119_372K | |
---|---|---|---|---|---|---|---|---|
Oselt. | −6.0 | −5.1 | −5.3 | −5.2 | −4.9 | −5.2 | −5.6 | −4.4 |
Zan. | −7.3 | −6.4 | −4.2 | −4.7 | −5.6 | −5.0 | −5.6 | −5.0 |
Per. | −7.7 | −6.6 | −5.3 | −5.4 | −5.6 | −5.6 | −5.1 | −5.3 |
Lan. | −6.6 | −6.3 | −4.7 | −4.6 | −5.5 | −5.0 | −4.9 | −4.6 |
L-Arg. | −5.1 | −5.0 | −4.6 | −4.4 | −4.4 | −4.4 | −4.5 | −4.7 |
Bens. | −5.1 | −4.9 | −5.0 | −5.0 | −5.2 | −5.0 | −5.4 | −5.4 |
R294 (4MWQ) | R294K | R119K | R372K | R294_119K | R294_372K | R119_372K | R294_119_372K | |
---|---|---|---|---|---|---|---|---|
Oselt. | Glu 120 Arg 153 Arg 372 Arg 294 | Arg 372 Arg 119 Arg 153 | Tyr 406 Arg 372 Arg 294 | Arg 294 Tyr 406 Arg 153 | Arg 372 Lys 294 | Arg 153 Arg 119 | Lys 119 Arg 153 Arg 294 | Lys 372 |
Zan. | Arg 372 Arg 119 Asn 296 Trp 180 Glu 229 Asp 152 | Tyr 406 Arg 372 Arg 119 Lys 294 Asp 152 Trp 180 | Trp 180 Arg 153 Tyr 406 Arg 294 Arg 372 | Trp 180 Arg 153 Glu 278 Arg 294 | Arg 372 Lys 294 Glu 278 | Tyr 406 Arg 119 Asp 152 Trp 180 Glu 278 | Glu 278 Arg 294 Tyr 406 Glu 229 Arg 153 Asp 152 | Lys 119 Glu 120 Asp 152 Glu 279 Lys 372 Tyr 406 |
Per. | Trp 180 Glu 229 Arg 153 Asp 152 Arg 119 Arg 372 Arg 294 Tyr 406 | Arg 119 Arg 372 Asp 152 Trp 180 Glu 229 Arg 153 | Trp 180 Arg 153 Arg 294 Tyr 406 Arg 372 | Arg 153 Arg 294 Tyr 406 | Asp 152 Arg 372 Lys 294 Tyr 406 | Lys 294 Lys 372 Tyr 406 Asp 152 | Glu 229 Trp 180 Arg 153 Tyr 406 Arg 294 | Lys 119 Lys 294 Tyr 406 Glu 120 Asp 152 Lys 372 |
Lan. | Arg 226 Glu 279 Arg 372 Glu 229 Arg 294 Tyr 406 Glu 278 Gly 349 | Arg 119 Arg 372 Asp 152 Trp 180 Arg 153 Glu 278 Lys 294 | Trp 180 Arg 153 Glu 278 Arg 294 Arg 372 Tyr 406 | Glu 278 Arg 294 Trp 180 Arg 153 | Arg 372 Glu 278 Lys 294 | Glu 278 Lys 294 Arg 119 Arg 153 Trp 180 Asp 152 | Tyr 406 Arg 294 Glu 278 Arg 153 Glu 229 Asp 152 | Lys 119 Glu 120 Lys 351 Lys 372 Tyr 406 Glu 427 |
L-Arg. | Arg 294 Arg 372 Glu 229 Trp 180 Asp 152 | Trp 180 Asp 152 Tyr 406 Arg 372 Arg 119 | Trp 180 Asp 152 Arg 372 Tyr 406 | Trp 180 Arg 153 Tyr 406 Arg 294 | Tyr 406 Arg 153 Asp 152 Trp 180 | Trp 180 Asp 152 Arg 119 | Tyr 406 Glu 229 Asp 152 Arg 153 Trp 180 Lys 119 | Glu 120 Tyr 406 Glu 427 |
Bens. | Trp 180 Glu 229 Asp 152 Tyr 406 Arg 119 Arg 372 | Arg 372 Lys 294 Tyr 406 Trp 180 Asp 152 Glu 229 | Trp 180 Asp 152 Lys 119 Arg 372 Tyr 406 | Trp 180 Arg 153 Tyr 406 Arg 294 | Tyr 406 Lys 294 Arg 153 Asp 152 Trp 180 | Arg 153 Trp 180 Glu 278 Lys 294 Tyr 406 | Asp 152 Trp 180 Glu 229 Tyr 406 Arg 294 | Trp 180 Arg 153 Asp 152 Tyr 406 Lys 294 |
R294 (4MWQ) | R294K (4MWW) | R119K | R372K | R294_119K | R294_372K | R119_372K | R294_119_372K | |
---|---|---|---|---|---|---|---|---|
Oselt. | Arg 119 Arg 294 Arg 372 | Arg 119 Arg 372 | Arg 294 Arg 372 | Arg 294 Lys 372 | Lys 294 Arg 372 | Arg 119 Lys 294 Lys 372 | Arg 294 | Lys 294 Lys 372 |
Zan. | Arg 119 Glu 120 Asp 152 Glu 229 Arg294 Arg 372 | Arg 119 Arg 372 Glu 120 Asp 152 Glu 229 | Glu 120 Asp152 Glu 229 Arg 294 Arg 372 | Arg 119 Glu 120 Asp 152 Glu 229 Lys 372 | Arg 372 | Arg 119 Glu 120 Asp 152 Glu 229 Lys 372 | Asp 152 Lys 372 | Asp 152 Glu 279 Lys 294 Lys 372 |
Per. | Arg 119 Glu 120 Asp 152 Glu 229 Arg 294 Arg 372 | Arg 119 Glu 120 Asp 152 Glu 229 Arg 372 | Glu 120 Asp 152 Glu 229 Arg 294 Arg 372 | Arg 119 Glu 120 Asp152 Glu 229 Arg 294 Lys 372 | Glu 120 Asp152 Glu 279 Lys 294 Arg 372 | Arg 119 Glu 120 Asp 152 Glu 279 Lys 372 | Asp 152 Arg 294 Lys 372 | Glu 120 Asp 152 Lys 294 Lys 372 |
Lan. | Arg 119 Glu 120 Asp 152 Glu 229 Arg 294 Arg 372 | Arg 119 Arg 372 Glu 120 Asp 152 Glu 229 | Arg 372 Glu 120 Asp 152 Glu 229 | Arg 119 Glu 120 Asp 152 Glu 229 Lys 372 | Glu 120 Asp 152 Arg 153 Glu 229 Glu 279 | Arg 119 Glu 120 Asp 152 Glu 229 Lys 372 | Glu 279 Arg 294 Lys 372 | Asp 152 Glu 279 Lys 294 Lys 372 |
L-Arg. | Arg 119 Glu 120 Glu 229 Glu 279 Arg 294 Arg 372 | Arg 119 Arg 372 Glu 120 Glu 279 Glu 229 | Arg 294 Arg 372 Glu 120 Asp 152 Glu 229 Glu 279 | Arg 119 Glu 120 Glu 229 Glu 279 Arg 294 Lys 372 | Glu 120 Glu 229 Glu 279 Arg 372 | Arg 119 Glu 120 Asp 152 Glu 229 Glu 279 Lys 372 | Asp 152 Lys 372 | Glu 120 Asp 152 Glu 229 Glu 279 Lys 372 |
Bens. | No Salt Bridge interactions | No Salt Bridge interactions | No Salt Bridge interactions | No Salt Bridge interactions | No Salt Bridge interactions | No Salt Bridge interactions | No Salt Bridge interactions | No Salt Bridge interactions |
Mutant N9 | Oseltamivir4MWQ | Zanamivir-4MWQ | Peramivir-4MWQ | Laninamivir-4MWQ | L-Arginine-4MWQ | Bens.-Hydrochl.-4MWQ |
---|---|---|---|---|---|---|
R294K (4MWW) | 1.0 | 0.8 | 0.8 | 0.5 | 1.2 | 2.2 |
R119K | 1.0 | 1.4 | 0.8 | 1.5 | 1.5 | 2.2 |
R372K | 2.7 | 1.6 | 0.9 | 1.5 | 4.1 | 2.7 |
R119_372K | 1.5 | 0.8 | 0.8 | 1.5 | 5.4 | 0.9 |
R294_119K | 6.4 | 7.3 | 4.6 | 5.2 | 5.9 | 6.1 |
R294_372K | 4.0 | 0.8 | 4.8 | 1.2 | 1.5 | 3.0 |
R294_119_372K | 10.8 | 0.7 | 4.6 | 5.2 | 6.6 | 3.6 |
Property | Model Name | Unit | Predicted Value | |||||
---|---|---|---|---|---|---|---|---|
Oselt. | Zan. | Per. | Lan. | L-arg. | Bens. | |||
Absorption | Water solubility | log mol/L | −2.4 | −2.9 | −2.9 | −2.9 | −2.9 | −2.2 |
Intestinal absorption (human) | % Absorbed | 74.5 | 21.2 | 26.8 | 27.4 | 34.5 | 36.2 | |
Skin permeability | log Kp | −3.2 | −2.7 | −2.7 | −2.7 | −2.7 | −2.7 | |
P-glycoprotein substrate | Yes/No | No | Yes | Yes | Yes | Yes | No | |
P-glycoprotein I inhibitor | Yes/No | No | No | No | No | No | No | |
P-glycoprotein II inhibitor | Yes/No | No | No | No | No | No | No | |
Distribution | VDss (human) | log L/kg | 0.04 | −0.08 | −0.03 | −0.2 | −0.002 | −0.2 |
Fraction unbound (human) | Fu | 0.6 | 0.4 | 0.4 | 0.4 | 0.4 | 0.9 | |
BBB permeability | log BB | −0.7 | −1.2 | −1.1 | −1.2 | −0.7 | −1.5 | |
CNS permeability | log PS | −3.1 | −4.7 | −4.4 | −4.4 | −4.0 | −4.8 | |
Metabolism | CYP2D6 substrate | Yes/No | No | No | No | No | No | No |
CYP3A4 substrate | Yes/No | No | No | No | No | No | No | |
CYP1A2 inhibitior | Yes/No | No | No | No | No | No | No | |
CYP2C19 inhibitior | Yes/No | No | No | No | No | No | No | |
CYP2C9 inhibitior | Yes/No | No | No | No | No | No | No | |
CYP2D6 inhibitior | Yes/No | No | No | No | No | No | No | |
CYP3A4 inhibitior | Yes/No | No | No | No | No | No | No | |
Excretion | Total Clearance | log ml/min/kg | 0.9 | 0.3 | −0.1 | 0.4 | 0.1 | 1.3 |
Renal OCT2 substrate | Yes/No | No | No | No | No | No | No | |
Toxicity | Ames toxicity | Yes/No | No | No | No | No | Yes | No |
Max. tolerated dose (human) | log mg/kg/day | 0.5 | 0.4 | 0.4 | 0.5 | 0.4 | 0.6 | |
hERG I inhibitor | Yes/No | No | No | No | No | No | No | |
hERG II inhibitor | Yes/No | No | No | No | No | No | No | |
Oral Rat Acute Toxicity (LD50) | mol/kg | 2.7 | 2.5 | 2.5 | 2.5 | 2.5 | 2.2 | |
Oral Rat Chronic Toxicity | log mg/kg_bw/day | 1.1 | 2.7 | 2.9 | 2.5 | 2.2 | 3.7 | |
Hepatotoxicity | Yes/No | No | No | No | No | No | Yes | |
Skin Sensitization | Yes/No | No | No | No | No | No | No | |
T. Pyriformis toxicity | log ug/L | 0.1 | 0.3 | 0.3 | 0.3 | 0.3 | 0.3 | |
Minnow toxicity | log mM | 2.3 | 5.8 | 3.0 | 5.3 | 3.3 | 3.9 |
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Sarukhanyan, E.; Shanmugam, T.A.; Dandekar, T. In Silico Studies Reveal Peramivir and Zanamivir as an Optimal Drug Treatment Even If H7N9 Avian Type Influenza Virus Acquires Further Resistance. Molecules 2022, 27, 5920. https://doi.org/10.3390/molecules27185920
Sarukhanyan E, Shanmugam TA, Dandekar T. In Silico Studies Reveal Peramivir and Zanamivir as an Optimal Drug Treatment Even If H7N9 Avian Type Influenza Virus Acquires Further Resistance. Molecules. 2022; 27(18):5920. https://doi.org/10.3390/molecules27185920
Chicago/Turabian StyleSarukhanyan, Edita, Tipack Ayothyapattanam Shanmugam, and Thomas Dandekar. 2022. "In Silico Studies Reveal Peramivir and Zanamivir as an Optimal Drug Treatment Even If H7N9 Avian Type Influenza Virus Acquires Further Resistance" Molecules 27, no. 18: 5920. https://doi.org/10.3390/molecules27185920