Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library
Abstract
:1. Introduction
2. Results and Discussion
2.1. Virtual Screening
2.2. Further Screening through Induced-Fit Docking
2.3. Pharmacophore Analysis
2.4. Molecular Dynamics Analysis
2.5. ADME/T Prediction
2.6. Compound Enzymatic Activity Assay
3. Materials and Methods
3.1. Experimental Procedures
3.2. Ligand Preparation
3.3. Protein Preparation and Grid Generation
3.4. Molecular Docking
3.5. MM-GBSA
3.6. Induced-Fit Docking (IFD)
3.7. Pharmacophore Analysis
3.8. ADME/T Prediction
3.9. Molecular Dynamics Analysis
3.10. In Vitro Enzymatic and Inhibition Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Rank | Compound | SP Docking Binding Energy (ΔG, kcal/mol) | XP Docking Binding Energy (ΔG, kcal/mol) | MM-GBSA dG Bind (kcal/mol) | IFD Binding Energy (kcal/mol) |
---|---|---|---|---|---|
1 | V247 | −8.538 | −7.976 | −63.43 | −11.34 |
2 | V253 | −8.832 | −7.97 | −62.15 | −12.787 |
3 | V133 | −8.379 | −7.969 | −58.29 | −10.76 |
4 | V109 | −7.567 | −7.108 | −68.64 | −12.342 |
5 | V212 | −7.688 | −7.038 | −47.32 | -- a |
6 | V131 | −7.876 | −6.759 | −67.51 | −9.919 |
7 | V254 | −7.286 | −6.665 | −57.63 | −10.896 |
8 | V248 | −7.565 | −6.645 | −46.39 | -- a |
9 | V282 | −7.481 | −6.564 | −49.38 | −9.959 |
10 | V139 | −7.422 | −6.49 | −54.66 | −9.584 |
11 | V231 | −7.372 | −6.453 | −57.18 | −10.961 |
12 | V128 | −7.264 | −6.422 | −59.99 | −9.557 |
13 | V160 | −7.241 | −6.409 | −58.19 | −10.191 |
14 | V163 | −7.052 | −6.337 | −52.59 | −9.817 |
15 | V174 | −7.369 | −6.293 | −56.94 | −10.993 |
16 | V243 | −7.68 | −6.267 | −60.64 | −11.459 |
17 | V229 | −7.509 | −6.237 | −57.48 | −9.365 |
18 | V204 | −7.89 | −6.229 | −53.3 | −9.652 |
19 | V291 | −8.071 | −6.225 | −59.08 | −9.628 |
20 | V228 | −8.122 | −6.12 | −56.37 | −10.792 |
21 | V170 | −7.085 | −6.118 | −50.4 | −10.11 |
22 | V215 | −7.032 | −6.08 | −45.32 | -- a |
23 | V165 | −7.051 | −6.078 | −48.72 | -- a |
24 | V75 | −7.331 | −6.072 | −56.99 | −10.714 |
25 | V205 | −7.501 | −6.029 | −47.89 | -- a |
26 | V120 | −7.081 | −6.025 | −51.7 | −9.171 |
27 | V222 | −7.305 | −6.018 | −48.47 | -- a |
28 | V245 | −7.401 | −6.008 | −56.32 | −10.098 |
29 | V226 | −7.141 | −6 | −61.64 | −11.774 |
30 | V159 | −7.091 | −5.995 | −46.69 | -- a |
31 | V12 | −7.192 | −5.987 | −48.94 | -- a |
32 | V225 | −7.068 | −5.983 | −48.31 | -- a |
33 | V252 | −7.416 | −5.981 | −57.86 | −11.603 |
34 | V219 | −7.212 | −5.972 | −43.13 | -- a |
35 | V173 | −7.138 | −5.965 | −47.29 | -- a |
36 | V241 | −7.108 | −5.963 | −39.62 | -- a |
37 | V154 | −7.26 | −5.93 | −49.83 | −10.761 |
38 | V304 | −7.878 | −5.911 | −54.47 | −9.512 |
39 | V230 | −7.314 | −5.891 | −43.13 | -- a |
40 | V172 | −7.403 | −5.85 | −50.46 | −11.391 |
41 | V97 | −7.138 | −5.825 | −60.03 | −11.778 |
42 | V111 | −7.195 | −5.823 | −49.62 | −10.706 |
43 | V238 | −7.134 | −5.811 | −55.55 | −10.605 |
44 | V155 | −7.113 | −5.77 | −48.22 | -- a |
45 | V112 | −7.29 | −5.744 | −44.36 | -- a |
46 | V60 | −7.261 | −5.637 | −49.07 | −10.191 |
47 | V257 | −7.37 | −5.637 | −48.64 | -- a |
48 | V103 | −7.535 | −5.55 | −60.98 | −9.795 |
49 | Nilotinib | −7.026 | −5.476 | −48.96 | −9.179 |
50 | V74 | −7.225 | −5.262 | -- a | -- a |
51 | V175 | −7.538 | −5.258 | -- a | -- a |
52 | V283 | −7.532 | −5.159 | -- a | -- a |
53 | V306 | −7.335 | −5.136 | -- a | -- a |
54 | V293 | −7.205 | −5.042 | -- a | -- a |
55 | V286 | −7.432 | −5.041 | -- a | -- a |
56 | V168 | −7.182 | −5.023 | -- a | -- a |
57 | V144 | −7.195 | −4.988 | -- a | -- a |
58 | V122 | −7.095 | −4.935 | -- a | -- a |
59 | V150 | −7.145 | −4.932 | -- a | -- a |
60 | V240 | −7.211 | −4.738 | -- a | -- a |
61 | V70 | −7.299 | −4.731 | -- a | -- a |
62 | V86 | −7.085 | −4.152 | -- a | -- a |
63 | V147 | −7.364 | −3.493 | -- a | -- a |
64 | V303 | −7.458 | −3.164 | -- a | -- a |
Compound | Molecular Interactions | Nature of Interactions | Distance (Å) |
---|---|---|---|
Nilotinib | Asn142:HD22-Lig:O1 | Hydrogen Bond | 2.56 |
Asn142:HD21-Lig:N6 | Hydrogen Bond | 2.33 | |
Cys145:HG-Lig:N5 | Hydrogen Bond | 2.48 | |
Lig:H16-His164:O | Hydrogen Bond | 2.58 | |
Lig:H9-Glu166:OE2 | Hydrogen Bond | 1.96 | |
Gln189:HE21-Lig:N6 | Hydrogen Bond | 2.01 | |
Gln189:HE22-Lig:O1 | Hydrogen Bond | 2.06 | |
V253 | Lig:N1-Glu166:OE2 | Salt bridge | 3.17 |
Lig:H19-Leu141:O | Hydrogen Bond | 1.97 | |
Gly143:H-Lig:O4 | Hydrogen Bond | 2.15 | |
Ser144:H-Lig:O4 | Hydrogen Bond | 2.68 | |
Cys145:H-Lig:O4 | Hydrogen Bond | 2.17 | |
Lig:H15-His164:O | Hydrogen Bond | 1.78 | |
Lig:H28-Glu166:OE2 | Hydrogen Bond | 2.43 | |
Lig:H11-Glu166:O | Hydrogen Bond | 2.62 | |
Gln189:HE21-Lig:O2 | Hydrogen Bond | 2.91 | |
Gln192:H-Lig:N3 | Hydrogen Bond | 3.17 | |
Gln192:HE21-Lig:N3 | Hydrogen Bond | 2.73 | |
His41-Lig | Hydrophobic (pi-pi Stacking) | 5.47 | |
His41-Lig | Hydrophobic (pi-pi Stacking) | 5.43 | |
V247 | Lig:N1-Glu166:OE2 | Salt bridge | 3.81 |
Asn142:HD21-Lig:O4 | Hydrogen Bond | 2.10 | |
Lig:H15-His164:O | Hydrogen Bond | 3.26 | |
Lig:H11-Glu166:O | Hydrogen Bond | 1.96 | |
Lig:H36-Glu166:O | Hydrogen Bond | 2.69 | |
Gln189:HE21-Lig:O1 | Hydrogen Bond | 1.96 | |
Gln192:HE21-Lig:N3 | Hydrogen Bond | 2.60 | |
V133 | Lig:N3-Glu166:OE2 | Salt bridge | 3.23 |
Gly143:H-Lig:O2 | Hydrogen Bond | 1.91 | |
Cys145:H-Lig:O2 | Hydrogen Bond | 3.33 | |
Lig:H28-Glu166:OE2 | Hydrogen Bond | 2.36 | |
Lig:H24-Glu166:O | Hydrogen Bond | 2.00 | |
Lig:H5-Arg188:O | Hydrogen Bond | 2.71 | |
Gln189:HE21-Lig:O1 | Hydrogen Bond | 1.98 | |
V228 | Lig:H1-His41:NE2 | Hydrogen Bond | 2.63 |
Asn142:H-Lig:O2 | Hydrogen Bond | 2.57 | |
Lig:H10-Asn142:OD1 | Hydrogen Bond | 1.98 | |
Lig:H1-His164:O | Hydrogen Bond | 3.10 | |
Lig:H21-Glu166:OE1 | Hydrogen Bond | 1.68 | |
His172:HE2-Lig:O3 | Hydrogen Bond | 3.14 | |
Gln189:HE21-Lig:O1 | Hydrogen Bond | 1.91 | |
Lig:H1-His41:NE2 | Hydrogen Bond | 2.63 | |
V291 | Lig:N2-Glu166:OE2 | Salt bridge | 4.88 |
Lig:H14-Thr26:O | Hydrogen Bond | 1.94 | |
Thr26:H-Lig:N7 | Hydrogen Bond | 2.92 | |
Lig:H12-His41:O | Hydrogen Bond | 2.24 | |
Lig:H19-Asn142:OD1 | Hydrogen Bond | 2.21 | |
Asn142:H-Lig:O1 | Hydrogen Bond | 2.62 | |
Gly143:H-Lig:N5 | Hydrogen Bond | 2.13 | |
Cys145:H-Lig:N5 | Hydrogen Bond | 3.00 | |
Lig:H2-Glu166:OE1 | Hydrogen Bond | 1.89 | |
Lig:H2-Glu166:OE2 | Hydrogen Bond | 3.07 | |
His41-Lig | Hydrophobic (pi-pi Stacking) | 4.40 | |
His41-Lig | Hydrophobic (pi-pi Stacking) | 4.58 | |
His163-Lig | Hydrophobic (pi-pi Stacking) | 5.26 |
Compounds | PSA | QPlogS | QPlogPo/w | donorHB | accptHB | CNS | #metab | Human Oral Absorption | QPlogBB | QPPMDCK | QPPCaco | QPlogHERG |
---|---|---|---|---|---|---|---|---|---|---|---|---|
V75 | 109.835 | −7.648 | 4.646 | 1 | 10.25 | −2 | 2 | 1 | −1.295 | 318.027 | 664.465 | −7.395 |
V97 | 108.109 | −7.351 | 4.096 | 1 | 10 | −2 | 2 | 1 | −1.35 | 469.306 | 338.538 | −7.096 |
V111 | 122.61 | −5.7 | 3.621 | 5 | 6.5 | −2 | 1 | 3 | −1.388 | 324.488 | 274.769 | −6.644 |
V131 | 118.105 | −9.052 | 5.627 | 2.25 | 8.25 | −2 | 4 | 1 | −1.183 | 1829.769 | 487.844 | −7.478 |
V133 | 121.912 | −7.656 | 4.886 | 2.25 | 10.25 | −1 | 5 | 1 | −0.944 | 458.546 | 123.765 | −8.379 |
V139 | 131.795 | −7.531 | 4.288 | 4 | 10 | −1 | 4 | 1 | −0.999 | 332.432 | 91.695 | −8.504 |
V159 | 89.316 | −8.698 | 6.02 | 1 | 8.5 | −1 | 1 | 1 | −0.568 | 3877.557 | 1007.174 | −7.822 |
V172 | 89.548 | −10.162 | 6.837 | 1 | 8.5 | −1 | 3 | 1 | −0.58 | 7550.982 | 849.164 | −8.139 |
V205 | 111.144 | −6.49 | 3.559 | 3 | 7.5 | −2 | 1 | 1 | −1.563 | 133.383 | 172.141 | −6.845 |
V222 | 127.504 | −5.182 | 3.093 | 5 | 7.25 | −1 | 2 | 3 | −1.731 | 101.888 | 231.806 | −6.597 |
V226 | 103.042 | −9.687 | 6.75 | 1.25 | 8.75 | −2 | 4 | 1 | −1.075 | 2761.001 | 715.442 | −7.297 |
V231 | 113.094 | −9.105 | 5.992 | 2.25 | 7.75 | −2 | 3 | 1 | −1.085 | 1992.813 | 528.81 | −7.326 |
V243 | 125.557 | −9.876 | 6.523 | 2.25 | 9 | −2 | 5 | 1 | −1.568 | 1356.918 | 372.469 | −7.538 |
V245 | 116.326 | −9.815 | 6.884 | 1.25 | 9.5 | −2 | 5 | 1 | −1.416 | 1933.915 | 514.511 | −7.371 |
V247 | 132.565 | −6.51 | 5.629 | 2.25 | 11 | −1 | 6 | 1 | −0.775 | 522.9 | 152.091 | −7.308 |
V253 | 143.489 | −7.077 | 4.417 | 2.25 | 10.95 | −2 | 6 | 1 | −1.538 | 184.545 | 53.315 | −8.299 |
V254 | 129.75 | −8.419 | 5.29 | 1.25 | 9.45 | −2 | 5 | 1 | −1.861 | 687.446 | 197.201 | −7.324 |
V282 | 123.041 | −6.679 | 3.535 | 3 | 10 | −1 | 2 | 1 | −0.581 | 408.384 | 110.962 | −7.606 |
V291 | 134.153 | −5.819 | 2.54 | 5 | 8 | −2 | 2 | 2 | −1.351 | 53.764 | 17.108 | −7.099 |
V304 | 129.939 | −5.218 | 2.33 | 4 | 9.5 | −1 | 4 | 2 | −0.865 | 146.26 | 23.945 | −6.2 |
Standard range | 7–200 | −6.5–0.5 | −2.0–6.5 | 0.0–6.0 | 2.0–20.0 | −2–+2 | 1–8 | 1, 2, or 3 for low, medium, or high | −3.0–1.2 | <25 poor, >500 great | <25 poor, >500 great | <−5 |
Compounds | Structure | IC50 Value (μM) |
---|---|---|
V111 | >20 | |
V139 | >20 | |
V159 | >20 | |
V205 | >20 | |
V226 | >20 | |
V231 | >20 | |
V243 | >20 | |
V291 | 2.77 ± 0.56 | |
V304 | >20 | |
Nilotinib | 19.92 ± 1.27 |
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Liu, N.; Yang, Z.; Liu, Y.; Dang, X.; Zhang, Q.; Wang, J.; Liu, X.; Zhang, J.; Pan, X. Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library. Int. J. Mol. Sci. 2023, 24, 11390. https://doi.org/10.3390/ijms241411390
Liu N, Yang Z, Liu Y, Dang X, Zhang Q, Wang J, Liu X, Zhang J, Pan X. Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library. International Journal of Molecular Sciences. 2023; 24(14):11390. https://doi.org/10.3390/ijms241411390
Chicago/Turabian StyleLiu, Nanxin, Zeyu Yang, Yuying Liu, Xintao Dang, Qingqing Zhang, Jin Wang, Xueying Liu, Jie Zhang, and Xiaoyan Pan. 2023. "Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library" International Journal of Molecular Sciences 24, no. 14: 11390. https://doi.org/10.3390/ijms241411390