Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Evaluation of Crystal Receptor-Ligand Complexes
2.2. Virtual Screening of World-Approved Drugs against hCA I
2.3. Toxicity Evaluation
2.4. Benchmark of Zn2+ Ion Models
2.5. MD Simulation of hCA I–Inhibitor Complexes and Binding Energy Calculations
2.6. Identification of Key Residues for Receptor–Inhibitor Interactions
2.7. Selectivity against hCA Isoforms
3. Materials and Methods
3.1. Docking Protocol
3.1.1. Receptor Preparation
3.1.2. Ligand Preparation
3.1.3. Docking Calculation
3.2. Toxicity Prediction
3.3. Simulation Protocol
3.3.1. Ligand-Free Systems
3.3.2. Receptor–Ligand Complexes
3.4. MM-PBSA Analysis
3.5. Inhibition against hCA Isoforms
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Res Name | PDB ID | Ligand Name | Molecular Structure | Crystal Complex | Docking Predictions | ||||
---|---|---|---|---|---|---|---|---|---|
∆E | d | ∆E | d | RMSD | Prob | ||||
949 | 5GMM | Polmacoxib | −8.0 | 1.95 | −9.0 | 3.41 | 3.95 | 1 | |
TOR | 3LXE | Topiramate | −7.5 | 2.00 | −8.5 | 2.73 | 4.35 | 1 | |
GZE | 6I0J | GZE | −7.8 | 2.00 | −8.5 | 2.55 | 0.73 | 0.7 | |
V14 | 5E2M | V14 | −5.7 | 1.95 | −8.2 | 2.91 | 1.36 | 1 | |
BZW | 6EVR | BZW | −7.0 | 1.94 | −8.1 | 4.96 | 1.34 | 1 | |
IWE | 7ZL5 | Diart | −6.0 | 1.98 | −8.0 | 2.86 | 1.12 | 1 | |
N19 | 6EX1 | N19 | −6.2 | 1.92 | −8.0 | 4.88 | 1.95 | 1 | |
D3B | 6FAF | D3B | −6.5 | 1.96 | −8.0 | 4.74 | 1.23 | 0.3 | |
3UG | 4WUQ | 3UG | −6.4 | 1.84 | −7.9 | 2.92 | 1.25 | 1 | |
CJK | 6F3B | CJK | −5.6 | 1.93 | −7.7 | 4.58 | 2.06 | 1 | |
O5N | 6XZY | O5N | −5.9 | 1.84 | −7.7 | 3.15 | 3.33 | 0.8 | |
EON | 6FAG | EON | −6.0 | 1.90 | −7.6 | 2.47 | 2.20 | 0.6 | |
O5H | 6XZX | O5H | −6.0 | 1.90 | −7.5 | 2.96 | 2.50 | 0.4 | |
84Z | 7Q0D | 84Z | −3.6 | 1.91 | −7.4 | 3.96 | 2.43 | 0.9 | |
O4Z | 6XZE | O4Z | −5.3 | 1.95 | −7.3 | 4.11 | 4.09 | 1 | |
O5K | 6XZS | O5K | −5.4 | 1.89 | −7.2 | 4.24 | 4.73 | 0.7 | |
3TV | 4WR7 | 3TV | −5.5 | 1.84 | −7.1 | 3.12 | 1.34 | 1 | |
O55 | 6XZO | O55 | −5.2 | 1.93 | −7.0 | 3.07 | 7.43 | 0.9 | |
7TI | 7PLF | Clorsulon | −4.4 | 1.94 | −6.9 | 2.85 | 3.23 | 1 | |
FLB | 3W6I | FLB | 1.9 | 5.06 | −6.8 | 7.31 | 3.19 | 1 | |
O5T | 6Y00 | O5T | −6.0 | 1.92 | −6.7 | 4.99 | 1.57 | 0.1 | |
M25 | 2NMX | M25 | −5.5 | 2.19 | −6.7 | 2.31 | 2.72 | 1 | |
M29 | 2NN7 | M29 | −5.4 | 2.11 | −6.6 | 2.36 | 3.22 | 1 | |
M28 | 2NN1 | M28 | −5.2 | 2.21 | −6.4 | 2.61 | 2.67 | 1 | |
AZM | 3W6H | Acetazolamide | −3.7 | 2.17 | −6.3 | 2.29 | 2.57 | 0.1 | |
MZM | 1BZM | Methazola-mide | −5.7 | 1.99 | −6.3 | 2.88 | 1.32 | 0.6 | |
AZM | 1AZM | Acetazola-mide | −5.3 | 2.01 | −5.9 | 3.68 | 2.22 | 1 | |
3UF | 4WUP | 3UF | −3.4 | 1.74 | −5.7 | 16.21 | 15.72 | 1 | |
FO9 | 6G3V | Famotidine | −3.6 | 1.95 | −5.7 | 16.82 | 15.52 | 1 | |
AAS | 1CZM | 3-Amabs | −3.9 | 1.86 | −5.6 | 2.42 | 2.24 | 1 | |
GZH | 6I0L | GZH | −4.2 | 1.92 | −5.5 | 3.96 | 1.84 | 1 | |
HIS | 2FW4 | d-histidine | −2.0 | 29.79 | −5.2 | 16.13 | 16.13 | 1 | |
PPF | 2IT4 | Foscarnet | −0.9 | 1.73 | −4.4 | 13.08 | 15.59 | 1 | |
EDO | 1JV0 | Ethylene glycol | −0.7 | 1.82 | −3.2 | 4.59 | 6.04 | 0.8 | |
BCT | 1HCB | Carbonate | −1.6 | 1.78 | −3.1 | 16.17 | 12.89 | 1 | |
EDO | 1J9W | Ethylene glycol | 0.1 | 1.75 | −1.7 | 14.26 | 13.57 | 1 |
ZINC ID | Name | Molecular Structure | q | ∆Edock | Toxicity | ||||
---|---|---|---|---|---|---|---|---|---|
Dili | Carcino | Immuno | Mutagen | Cyto | |||||
ZINC000011681563 | Netupitant | 0 | −9.9 | N(66) | N(71) | N(78) | N(73) | N(64) | |
ZINC000011681563 | Netupitant | 1 | −9.9 | N(66) | N(71) | N(78) | N(73) | N(64) | |
ZINC000000601301 | Bhft | 0 | −9.8 | N82) | N(71) | N(89) | N(84) | N73) | |
ZINC000205224698 | Pronetupitant | 1 | −9.8 | N(66) | N(58) | N(53) | N(55) | N(61) | |
ZINC000027990463 | Lomitapide | 1 | −9.7 | N(78) | N(61) | N(70) | N(58) | N(77) | |
ZINC000021981256 | 8-hydroxymirtazapine | 1 | −9.6 | N(83) | N(66) | N(96) | N(61) | N(59) | |
ZINC000003816514 | Rolapitant | 0 | −9.6 | N(83) | N(66) | N(93) | N(67) | N(75) | |
ZINC000003816514 | Rolapitant | 1 | −9.6 | N(83) | N(66) | N(93) | N(67) | N(75) | |
ZINC000022034381 | Lidoflazine | 0 | −9.5 | N(79) | N(70) | N(97) | N(78) | N(67) | |
ZINC000031417974 | Ketoprofen glucuronide | −1 | −9.3 | N(71) | N(68) | N(85) | N(85) | N(82) | |
ZINC000002570882 | 4-hydroxyalprazolam | 0 | −9.2 | N(52) | N(67) | N(97) | N(74) | N(70) | |
ZINC000000607726 | Bemetizide | 0 | −9.2 | N(89) | N(76) | N(88) | N(92) | N(81) | |
ZINC000022034381 | Lidoflazine | 1 | −9.2 | N(79) | N(70) | N(97) | N(78) | N(67) | |
ZINC000100036907 | Cyclothiazide | 0 | −9.1 | N(91) | N(74) | N(91) | N(88) | N(73) | |
ZINC000000589683 | Polmacoxib | 0 | −9.0 | N(53) | N(62) | N(89) | N(70) | N(67) | |
ZINC0000005843546 | Diart | 0 | −8.0 | N(59) | N(53) | N(95) | N(69) | N(62) | |
ZINC0000263621146 | 3UG | 0 | −7.9 | N(66) | N(58) | N(99) | N(81) | N(69) | |
84Z | 0 | −7.4 | N(65) | N(67) | N(99) | N(75) | N(70) |
Legend | Force Field | Zn2+ Model | RMSDbackbone | RMSDmetal | Zn2+–Ligand Distance (Å) | CNZn | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
Parameter Set | R | ε | Ref | (Å) | (Å) | NE2 (H94) | NE2 (H96) | ND1 (H119) | |||
a14SB-Merz | ff14SB | Merz | 1.1 | 0.0125 | [50] | 1.25 ± 0.08 | 0.62 ± 0.05 | 2.25 ± 0.14 | 2.54 ± 0.19 | 4.71 ± 0.17 | 4.4 |
a14SB-Merz-constraints | ff14SB | Merz (constraints) | 1.1 | 0.0125 | [50] | 1.37 ± 0.12 | 0.26 ± 0.04 | 1.98 ± 0.01 | 2.02 ± 0.01 | 2.02 ± 0.01 | 6.0 |
a14SB-HFE | ff14SB | HFE set by Li et al. | 1.175 | 0.00071558 | [51] | 1.55 ± 0.19 | 1.05 ± 0.37 | 28.57 ± 1.45 | 26.31 ± 1.25 | 25.69 ± 1.54 | 3.0 |
a14SB-IOD | ff14SB | IOD set by Li et al. | 1.395 | 0.014917 | [51] | 1.38 ± 0.08 | 0.28 ± 0.05 | 2.17 ± 0.07 | 2.18 ± 0.07 | 2.28 ± 0.09 | 6.0 |
a14SB-CM | ff14SB | CM set by Li et al. | 1.271 | 0.00330286 | [51] | 1.32 ± 0.12 | 0.91 ± 0.16 | 5.00 ± 0.80 | 2.20 ± 0.13 | 6.10 ± 0.83 | 6.0 |
a14SB-Zhang | ff14SB | Zhang et al. | 0.5152 | 295.5289 | [52] | 1.21 ± 0.08 | 0.65 ± 0.14 | 4.57 ± 0.59 | 2.20 ± 0.05 | 4.55 ± 0.28 | 7.0 |
a99SB-Macchiagodena | ff99SB-ILDN | Macchiagodena et al. | 1.4561 | 0.0125 | [53,54] | 1.69 ± 0.10 | 0.36 ± 0.07 | 2.12 ± 0.05 | 2.12 ± 0.05 | 2.09 ± 0.04 | 6.0 |
a14SB-Macchiagodena | ff14SB | Macchiagodena et al. | 1.4561 | 0.0125 | [53,54] | 1.46 ± 0.09 | 0.36 ± 0.06 | 2.12 ± 0.05 | 2.12 ± 0.05 | 2.09 ± 0.04 | 6.0 |
crystal-7q0d | 1.97 | 2.02 | 2.02 | 4.0 |
Ligand Name | q | dML | Ligand Atom | dbound | ||
---|---|---|---|---|---|---|
Initial | MD | Initial | MD | |||
Netupitant | 0 | 1.04 | 1.59 ± 0.11 | F6 | 2.95 | 12.97 ± 2.24 |
Netupitant | 1 | 1.14 | 2.93 ± 0.56 | F6 | 3.14 | 27.7 ± 5.63 |
Bhft | 0 | 0.9 | 0.92 ± 0.03 | O1 | 2.53 | 2.33 ± 0.15 |
N1 | 4.73 | 2.31 ± 0.12 | ||||
Pronetupitant | 0 | 1.12 | 2.09 ± 0.34 | F6 | 2.83 | 17.81 ± 5.85 |
Lomitapide | 1 | 1.15 | 1.91 ± 0.38 | F2 | 2.82 | 16.57 ± 4.75 |
8-hydroxymirtazapine | 1 | 0.92 | 2.58 ± 0.71 | O1 | 2.55 | 27.58 ± 6.54 |
Rolapitant | 0 | 0.95 | 1.61 ± 0.11 | F6 | 3.47 | 11.82 ± 1.98 |
Rolapitant | 1 | 0.94 | 1.49 ± 0.09 | F5 | 2.67 | 11.01 ± 1.41 |
Lidoflazine | 0 | 0.96 | 1.42 ± 0.06 | F1 | 2.88 | 4.37 ± 0.24 |
Ketoprofen glucuronide | −1 | 0.99 | 1.08 ± 0.02 | O4 | 3.22 | 2.08 ± 0.06 |
4-hydroxyalprazolam | 0 | 0.85 | 1.95 ± 0.04 | N1 | 2.92 | 14.79 ± 0.63 |
Bemetizide | 0 | 0.81 | 0.85 ± 0.03 | N2 | 2.30 | 2.31 ± 0.12 |
Lidoflazine | 1 | 0.96 | 1.34 ± 0.13 | F1 | 2.80 | 4.63 ± 0.30 |
Cyclothiazide | 0 | 0.85 | 0.81 ± 0.02 | N1 | 2.47 | 4.43 ± 0.24 |
O2 | 2.60 | 2.44 ± 0.21 | ||||
Polmacoxib | 0 | 0.89 | 0.91 ± 0.04 | N1 | 1.95 | 4.62 ± 0.19 |
O3 | 2.88 | 2.33 ± 0.17 | ||||
Diart | 0 | 0.81 | 1.32 ± 0.15 | N5 | 1.98 | 10.39 ± 1.46 |
3UG | 0 | 0.82 | 0.83 ± 0.02 | N1 | 1.84 | 2.30 ± 0.10 |
84Z | 0 | 0.84 | 0.86 ± 0.02 | N1 | 1.91 | 4.39 ± 0.22 |
O3 | 2.99 | 2.29 ± 0.13 |
Compound | q | ΔEvdW | ΔEelec | ΔEMM | ΔGpolar | ΔGnonpolar | ΔEbind |
---|---|---|---|---|---|---|---|
84Z | 0 | −34.25 ± 1.17 | −43.15 ± 2.00 | −77.4 ± 2.15 | 63.13 ± 1.51 | −3.57 ± 0.03 | −17.84 ± 1.80 |
Cyclothiazide | 0 | −39.51 ± 1.27 | −38.52 ± 1.85 | −78.03 ± 2.20 | 65.26 ± 2.43 | −3.44 ± 0.03 | −16.21 ± 1.85 |
3UG | 0 | −24.81 ± 0.56 | −58.7 ± 0.61 | −83.5 ± 0.55 | 72.45 ± 0.95 | −2.93 ± 0.02 | −13.99 ± 0.40 |
Bhft | 0 | −33.44 ± 0.70 | −68.73 ± 1.72 | −102.16 ± 0.92 | 96.57 ± 1.57 | −3.73 ± 0.05 | −9.33 ± 2.04 |
Ketoprofen glucuronide | −1 | −35.30 ± 0.29 | −183.62 ± 2.00 | −218.92 ± 0.78 | 213.98 ± 0.88 | −4.17 ± 0.01 | −9.12 ± 0.55 |
Polmacoxib | 0 | −26.56 ± 0.45 | −27.71 ± 2.57 | −54.28 ± 1.15 | 54.70 ± 1.67 | −3.40 ± 0.02 | −2.98 ± 0.46 |
Bemetizide | 0 | −32.23 ± 1.69 | −31.56 ± 3.37 | −63.78 ± 2.21 | 68.27 ± 7.94 | −3.61 ± 0.12 | 0.87 ± 2.80 |
Name | Identifier | 84Z | Cyclothiazide | 3UG |
---|---|---|---|---|
hCA I | 7Q0D | −8.0 ± 0.1 | −9.1 ± 0.1 | −7.9 ± 0.1 |
hCA II | 1BCD | −8.0 ± 0.1 | −8.3 ± 0.1 | −7.4 ± 0.1 |
hCA III | 3UYN | −6.8 ± 0.1 | −7.5 ± 0.1 | −6.8 ± 0.1 |
hCA IV | 5IPZ | −6.9 ± 0.1 | −6.5 ± 0.2 | −6.2 ± 0.1 |
hCA VA | AF-P35218-F1 | −6.2 ± 0.1 | −6.9 ± 0.1 | −5.8 ± 0.2 |
hCA VB | AF-Q9Y2D0-F1 | −7.0 ± 0.1 | −7.6 ± 0.2 | −6.7 ± 0.1 |
hCA VI | 3FE4 | −6.0 ± 0.1 | −7.1 ± 0.1 | −6.1 ± 0.1 |
hCA VII | 6H37 | −7.2 ± 0.1 | −8.1 ± 0.1 | −7.4 ± 0.1 |
hCA IX | 6FE1 | −7.5 ± 0.1 | −8.2 ± 0.1 | −7.3 ± 0.1 |
hCA XII | 1JD0 | −7.1 ± 0.2 | −7.6 ± 0.3 | −6.9 ± 0.1 |
hCA XIII | 4KNM | −7.8 ± 0.1 | −8.9 ± 0.1 | −7.9 ± 0.1 |
hCA XIV | 4LU3 | −7.8 ± 0.1 | −8.3 ± 0.1 | −7.3 ± 0.1 |
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Zheng, N.; Jiang, W.; Zhang, P.; Ma, L.; Chen, J.; Zhang, H. Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study. Int. J. Mol. Sci. 2023, 24, 12619. https://doi.org/10.3390/ijms241612619
Zheng N, Jiang W, Zhang P, Ma L, Chen J, Zhang H. Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study. International Journal of Molecular Sciences. 2023; 24(16):12619. https://doi.org/10.3390/ijms241612619
Chicago/Turabian StyleZheng, Nannan, Wanyun Jiang, Puyu Zhang, Le Ma, Junzhao Chen, and Haiyang Zhang. 2023. "Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study" International Journal of Molecular Sciences 24, no. 16: 12619. https://doi.org/10.3390/ijms241612619