Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparation of SARS-CoV-2 Mpro Receptors for Docking
2.2. Preparation of Ligands for Docking into SARS-CoV-2 Mpro
2.3. Docking Ligands into the SARS-CoV-2 Mpro Receptor
2.4. Structural Evaluation of SARS-CoV-2 Mpro Receptors
2.5. Conservation Analysis of SARS-CoV-2 Mpro Receptor
2.6. Calculation of Physiochemical Properties and Bioactivity
2.7. Molecular Dynamics of CM02, CM06, and CM07 Complex with SARS-CoV-2 Mpro Receptor (6LU7)
3. Results and Discussion
3.1. The SARS-CoV-2 Mpro Active Site
3.2. Docking of Bound Zinc Database Inhibitors in Coronavirus Receptors
3.3. Halogens in the SARS-CoV-2 Mpro Actives Site Have Little Impact on Binding Affinity
3.4. Addition of Aliphatic Substituents Increases Binding Affinity to SARS-CoV-2 Mpro Receptor
3.5. Nitrogen Heterocycles can Increase Binding Affinity to SARS-CoV-2 Active Site
3.6. Aliphatic Rings Improve Binding Afinity to SARS-CoV-2 Mpro Active Site
3.7. Several Hydrogen Bonding Hotspots are Present in SARS-CoV-2 Mpro
3.8. Design of Compounds with Optimized Binding Affinity to SARS-CoV-2 Mpro
3.9. Optimization of Cinanserin Hit for SARS-CoV-2 Mpro
3.10. Molecular Dynamics of CM02, CM06, and CM07 for SARS-CoV-2 Mpro (PDB ID: 6LU7)
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Residue Position | Subsite | Residue in SARS-CoV-2 Mpro | Residue Variety |
---|---|---|---|
49 | S2 | Met | Leu, Ala, Met, Tyr, Ser, Phe, Asn, Thr |
50 | S2 | Leu | Val, Thr, Asn, Gln, Lys, His, Ser, Arg, Met, Ala, Leu |
190 | S4 | Thr | Thr, Val, Lys, Asn, Cys, Ile, Arg, Ser, Leu |
191 | S4 | Ala | Val, Ile, Pro, Phe, His, Tyr, Ser, Met, Leu, Ala |
193 | S4 | Val | Lys, Asn, Gln, Ile, Val, Ala, Leu, Met, Phe, Arg, His, Ser |
Zinc Database Inhibitor | PDB File of Compound | Abbreviated Compound Name in PDB File | Docking Score −log10(Kd) |
---|---|---|---|
Z1587220559 | 5REC | T1J | 5.92 |
Z271004858 | 5RF8 | SFY | 5.42 |
PCM-0102269 | 5RET | T47 | 4.69 |
Z1271660837 | 5RFB | K3S | 3.80 |
PCM-0102575 | 5RFK | T7D | 3.47 |
Compound | Highest Docking Score −log10(Kd) |
---|---|
T1J G-series | 5.92 |
GM03 | 5.64 |
GN01 | 5.43 |
GN02 | 5.39 |
GM10 | 4.82 |
T47 chair B-series | 4.69 |
BM26 | 4.68 |
BD11 | 4.66 |
BD23 | 4.43 |
BM24 | 4.17 |
BD22 | 4.25 |
BM25 | 4.08 |
Compound | Highest Docking Score −log10(Kd) | Substituent Added | Compound | Highest Docking Score −log10(Kd) | o, m, p | Substituent Added |
---|---|---|---|---|---|---|
HS04 | 6.30 | Butyl | SD12 | 7.62 | m | Butyl |
BD03 | 5.92 | SD11 | 7.28 | m | Propyl | |
HS03 | 5.68 | Propyl | SD23 | 7.17 | m | Neopentyl |
BD02 | 5.41 | SD15 | 7.16 | p | Propyl | |
BD01 | 5.40 | SD27 | 7.04 | m | Butenyl | |
HS01 | 5.05 | Methyl | SD28 | 6.79 | p | Butenyl |
HS02 | 4.95 | Ethyl | SD07 | 6.66 | o | Propyl |
T47 | 4.69 | SD08 | 6.53 | o | Butyl | |
SD24 | 6.45 | p | Neopentyl | |||
SD16 | 6.35 | p | Butyl | |||
SD14 | 6.20 | p | Ethyl | |||
SD26 | 6.10 | o | Butenyl | |||
SD09 | 6.10 | m | Methyl | |||
SD22 | 6.07 | o | Neopentyl | |||
SD10 | 5.95 | m | Ethyl | |||
SD13 | 5.88 | p | Methyl | |||
SD06 | 5.70 | o | Ethyl | |||
SD05 | 5.51 | o | Methyl | |||
SFY | 5.42 |
Compound | Highest Docking Score −log10(Kd) | Compound | Highest Docking Score −log10(Kd) |
---|---|---|---|
DB04 | 6.88 | SD29 | 7.72 |
DB09 | 6.76 | SD25 | 7.19 |
DB11 | 6.77 | SD19 | 6.83 |
DB03 | 6.65 | SD31 | 6.68 |
DB12 | 6.33 | SD18 | 6.21 |
DB02 | 6.32 | SD20 | 5.46 |
DB10 | 6.22 | SFY | 5.42 |
DB08 | 5.97 | SD30 | 5.42 |
DB05 | 5.53 | SD17 | 5.40 |
DB06 | 5.39 | SD32 | 4.69 |
T47 | 4.69 | SD33 | 4.31 |
Compound | Highest Docking Score −log10(Kd) | OMP | Substituent(s) | Compound | Highest Docking Score −log10(Kd) |
---|---|---|---|---|---|
SD34 | 11.02 | M/P | Butyl/butyl | KT11 | 7.00 |
LEA4 | 10.94 | O/P | Butyl/butyl | E010 | 6.97 |
LEA2 | 10.02 | O/P | Propyl/propyl | KT10 | 6.36 |
KT04 | 9.92 | P | Butyl | KT14 | 6.09 |
KTH1 | 9.82 | O/P | Ethyl/butyl | KT12 | 5.72 |
KTH3 | 9.82 | Butyl/cyclohexyl | EW10 | 5.52 | |
SD35 | 9.72 | M/P | Propyl/propyl | EW01 | 4.36 |
KTH2 | 9.64 | O/P | Methyl/butyl | EW06 | 4.27 |
LEA3 | 9.54 | O/P | Ethyl/ethyl | EW08 | 4.17 |
SD04 | 9.41 | M | Butyl | K3S | 3.80 |
SD03 | 9.33 | M | Propyl | EW07 | 3.69 |
SD36 | 9.21 | M/P | Ethyl/ethyl | ||
KT03 | 9.21 | P | Propyl | ||
LM03 | 9.12 | O | Butyl | ||
LEA1 | 8.81 | O/P | Methyl/methyl | ||
L006 | 8.75 | O | Propyl | ||
KT02 | 8.71 | P | Ethyl | ||
SD37 | 8.62 | M/P | Methyl/methyl | ||
SD02 | 8.52 | M | Ethyl | ||
L005 | 8.10 | O | Ethyl | ||
L001 | 8.26 | ||||
LM02 | 8.28 | ||||
KT01 | 7.91 | P | Methyl | ||
SD01 | 7.83 | M | Methyl | ||
SD21 | 7.74 | ||||
L004 | 7.60 | O | Methyl | ||
SFY | 5.42 |
Compound | Highest Docking Score −log10(Kd) | Compound | Highest Docking Score −log10(Kd) |
---|---|---|---|
KF08 | 8.80 | JN16 | 8.16 |
KF03 | 8.07 | JMH5 | 7.42 |
KF04 | 7.14 | JN14 | 6.00 |
KF07 | 6.90 | JCN6 | 5.82 |
KF01 | 6.77 | JCN8 | 5.79 |
KF02 | 6.66 | JN12 | 5.61 |
GN06 | 6.41 | JN10 | 5.28 |
T1J | 5.92 | T7DM | 3.77 |
GN07 | 5.67 | T7D | 3.47 |
GM09 | 5.61 | ||
KF05 | 5.52 | ||
EW13 | 7.33 | HS06 | 7.85 |
EW14 | 7.32 | HS05 | 7.03 |
EW11 | 6.99 | T47 | 4.69 |
Compound | Highest Docking Score −log10(Kd) | LogP | LogS |
---|---|---|---|
FL30 | 13.98 | 1.62 | −4.27 |
FL20 | 13.17 | 1.44 | −3.76 |
FL29 | 12.98 | 4.39 | −5.51 |
FL28 | 12.98 | 1.62 | −4.01 |
FL23 | 12.96 | 4.25 | −5.38 |
FL26 | 12.67 | 4.35 | −5.56 |
FL16 | 12.41 | 0.79 | −3.23 |
FL22 | 12.32 | 1.43 | −3.72 |
FL24 | 12.30 | 4.23 | −5.32 |
KBH1 | 11.31 | 1.96 | −5.48 |
FL05 | 11.11 | 0.45 | −2.67 |
FL18 | 11.09 | 1.00 | −3.56 |
FL14 | 10.83 | 1.15 | −3.65 |
FL09 | 10.62 | 0.63 | −2.82 |
FL04 | 10.60 | 0.45 | −2.64 |
FL21 | 10.50 | 2.00 | −3.58 |
KB01 | 10.46 | 0.90 | −4.46 |
FL27 | 10.44 | 0.58 | −2.87 |
FL31 | 10.27 | 1.39 | −3.79 |
FL15 | 10.10 | 1.13 | −3.65 |
FL06 | 10.05 | 0.86 | −2.91 |
FL08 | 9.92 | 0.11 | −2.38 |
FL07 | 9.82 | 0.14 | −2.38 |
FL25 | 9.42 | 0.29 | −2.84 |
FL03 | 9.26 | 1.26 | −3.36 |
T1J | 5.92 | 2.83 | −3.16 |
SFY | 5.42 | 0.84 | −3.03 |
T47 | 4.69 | 1.73 | −2.02 |
K3S | 3.80 | −0.27 | −1.43 |
T7D | 3.47 | 1.73 | −2.02 |
Inhibitor Name | Highest Docking Score −log10(Kd) | LogP | LogS | MW | Topological Polar Surface Area | Protease Bioactivity Score |
---|---|---|---|---|---|---|
CM06 | 10.60 | 3.61 | −5.74 | 402.61 | 80.91 | 0.51 |
CM07 | 9.12 | 3.75 | −6.03 | 410.59 | 93.17 | 0.11 |
CM02 | 8.98 | 5.23 | −6.12 | 416.63 | 75.35 | 0.46 |
CO08 | 8.95 | 5.51 | −6.54 | 404.63 | 55.12 | 0.49 |
CM05 | 8.42 | 4.39 | −6.13 | 417.25 | 58.36 | 0.56 |
CM01 | 8.29 | 2.66 | −4.58 | 407.67 | 58.36 | 0.76 |
CO09 | 8.19 | 5.51 | −6.55 | 400.63 | 55.12 | 0.47 |
CO03 | 8.15 | 3.41 | −5.06 | 367.60 | 58.36 | 0.60 |
CO04 | 8.05 | 2.53 | −4.85 | 361.56 | 58.36 | 0.46 |
CO10 | 7.28 | 5.84 | −6.63 | 394.58 | 55.12 | 0.21 |
Cinanserin | 6.01 | 4.27 | −5.24 | 340.49 | 32.34 | −0.10 |
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Stoddard, S.V.; Stoddard, S.D.; Oelkers, B.K.; Fitts, K.; Whalum, K.; Whalum, K.; Hemphill, A.D.; Manikonda, J.; Martinez, L.M.; Riley, E.G.; et al. Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site. Viruses 2020, 12, 942. https://doi.org/10.3390/v12090942
Stoddard SV, Stoddard SD, Oelkers BK, Fitts K, Whalum K, Whalum K, Hemphill AD, Manikonda J, Martinez LM, Riley EG, et al. Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site. Viruses. 2020; 12(9):942. https://doi.org/10.3390/v12090942
Chicago/Turabian StyleStoddard, Shana V., Serena D. Stoddard, Benjamin K. Oelkers, Kennedi Fitts, Kellen Whalum, Kaylah Whalum, Alexander D. Hemphill, Jithin Manikonda, Linda Michelle Martinez, Elizabeth G. Riley, and et al. 2020. "Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site" Viruses 12, no. 9: 942. https://doi.org/10.3390/v12090942
APA StyleStoddard, S. V., Stoddard, S. D., Oelkers, B. K., Fitts, K., Whalum, K., Whalum, K., Hemphill, A. D., Manikonda, J., Martinez, L. M., Riley, E. G., Roof, C. M., Sarwar, N., Thomas, D. M., Ulmer, E., Wallace, F. E., Pandey, P., & Roy, S. (2020). Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site. Viruses, 12(9), 942. https://doi.org/10.3390/v12090942