Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics
Abstract
:1. Introduction
2. Results and Discussion
2.1. WT-MRP4, G187W, and Y556C Model Building and CG-MD Simulations
2.2. Molecular Docking in MRP4 and Variants
2.3. Differences in the Interaction Pattern in MRP4 Structures
2.4. All-Atom Molecular Dinaymics (AA-MD) Simulations and Umbrella Sampling Studies
3. Materials and Methods
3.1. Protein Threading for WT-MRP4 and Its Variants G187W and Y556C
3.2. Coarse-Grained Molecular Dynamics (CG-MD) Simulations
3.3. Molecular Docking on WT-MRP4, G187W and Y556C
3.4. All-Atom Molecular Dynamics (AA-MD) Simulations
3.5. Umbrella Sampling
3.6. Manipulation of the Complexes and Figures
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Endogen Substrate | WT-MRP4 | G187W | Y556C |
---|---|---|---|
cAMP | −5.88 | −6.35 | −5.82 |
Cholic acid | −10.55 | −7.2 * | −8.51 * |
Folic acid | −8.56 | −1.51 * | −2.39 * |
Glycolic acid | −7.35 | −9.09 * | −5.42 * |
Leukotriene B4 | −8.19 | −7.82 | −6.07 * |
PGE1 | −8.21 | −7.31 | −7.48 |
PGE2 | −7.36 | −7.31 | −7.00 |
Prasterone sulphate | −10.65 | −9.24 * | −9.57 * |
Taurocholic acid | −4.61 | −9.9 * | −6.07 * |
Uric acid | −4.77 | −5.13 | −5.06 |
Drug Substrate | WT-MRP4 | G187W | Y556C |
---|---|---|---|
6-Mercaptopurine | −4.34 | −5.06 | −4.81 |
Adefovir | −3.54 | −2.88 | −4.42 |
Cefazoline | −8.71 | −5.65 * | −10.12 * |
Cefotaxime | −7.04 | −6.08 | −6.88 |
Ceftizoxime | −7.02 | −7.16 | −6.59 |
Furosemide | −5.77 | −5.52 | −7.00 * |
Hydrochlorothiazide | −6.70 | −6.39 | −6.73 |
Leucovorin | −6.46 | −6.60 | −3.78 * |
Methotrexate | −6.98 | −7.22 | −3.76 * |
Olmesartan | −7.30 | −8.75 * | −7.4 |
Tenofovir | −2.76 | −3.15 | −4.58 * |
Topotecan | −6.09 | −6.39 | −8.26 * |
Inhibitors | WT-MRP4 | G187W | Y556C |
---|---|---|---|
ABSF | –5.41 | –5.85 | –5.97 |
Artesunate | –6.02 | –5.42 | –6.59 |
Ceefourin1 | –7.52 | –6.19 * | –7.22 |
Celecoxib | –7.57 | –8.16 | –7.98 |
Dipyridamole | –3.86 | –4.78 | –4.23 |
Glafenine | –8.27 | –5.48 * | –6.32 * |
Indomethacin | –8.42 | –7.07 * | –8.43 |
Losartan | –8.82 | –8.91 | –6.55 * |
MK-571 | –8.86 | –9.65 | –8.87 |
Parthenolide | –7.88 | –6.92 | –7.67 |
Prazosin | –6.71 | –6.98 | –7.25 |
Probenecid | –6.59 | –5.89 | –6.34 |
Quercetin | –6.16 | –6.2 | –6.63 |
Sildenafil | –7.67 | –8.43 * | –8.25 |
Sulindac | –8.41 | –7.82 | –8.41 |
Tyrphostin | –7.74 | –7.32 | –8.11 |
WT-MRP4 | G187W | Y556C | |
---|---|---|---|
Endogen substrates | Glu 1002, Lys 702, Thr 839, Lys 106, Lys 329, Glu 374, Gln 251, Phe 698 | Arg 946, Arg 998. Gly 991, Lys 702, Arg 946 | Arg 951, Trp 947, Glu 7, Gln 6, Val4 |
Drug substrates | Arg 946, Arg 998, Lys 702, arg 946, Thr 994, arg 312, Lys 329, Phe 698 | Ser 945, Lys 329, Leu 987, Arg 946, Arg 951, Arg 312, Ser 306 | Arg 946, Asp 15, Phe 329, Lys 32, Phe 939 |
Inhibitors | Phe 993, Pro 867, Arg 951, Arg 362, Thr 366, Gln 251, Leu 247 | Phe 325, Lys 329, Thr 364, Glu 102, Glu 103, Trp 995 | Phe 993, Pro 867, Arg 951, Trp 947 |
ΔG (kcal/mol) | |||
---|---|---|---|
Ligand | WT-MRP4 | G187W | Y556C |
FA | –25.340 | –23.288 | –46.4898 |
FA-ATP | −16.490 | −23.429 | −38.9452 |
FA-ATP1 | −46.010 | −29.343 | −18.7461 |
FA-ATP2 | −37.226 | −18.690 | −61.100 |
cAMP | −17.700 | −31.014 | −12.5676 |
cAMP-ATP | −17.721 | −39.300 | −31.560 |
cAMP-ATP1 | −43.966 | −33.690 | −49.7395 |
cAMP-ATP2 | −23.860 | −47.230 | −38.5368 |
Ceefourin-1 | −25.9938 | −33.8589 | −18.8326 |
Ceefourin-1-ATP | −22.9107 | −19.7664 | −22.5503 |
Ceefourin-1-ATP1 | −40.9182 | −43.1199 | −43.1179 |
Ceefourin-1-ATP2 | −37.2706 | −52.9313 | −53.6592 |
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Becerra, E.; Aguilera-Durán, G.; Berumen, L.; Romo-Mancillas, A.; García-Alcocer, G. Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics. Molecules 2021, 26, 1051. https://doi.org/10.3390/molecules26041051
Becerra E, Aguilera-Durán G, Berumen L, Romo-Mancillas A, García-Alcocer G. Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics. Molecules. 2021; 26(4):1051. https://doi.org/10.3390/molecules26041051
Chicago/Turabian StyleBecerra, Edgardo, Giovanny Aguilera-Durán, Laura Berumen, Antonio Romo-Mancillas, and Guadalupe García-Alcocer. 2021. "Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics" Molecules 26, no. 4: 1051. https://doi.org/10.3390/molecules26041051