Identification of Potential Allosteric Site Binders of Indoleamine 2,3-Dioxygenase 1 from Plants: A Virtual and Molecular Dynamics Investigation
Abstract
:1. Introduction
1.1. Tryptophan Metabolism and the Kynurenine Pathway
1.2. IDO1: Structure
- apo-IDO1: without the heme cofactor;
- holo-IDO1: containing the iron atom of the heme group in the ferric state (Fe3+);
- holo-IDO1 with the iron atom of the heme group in the ferrous state (Fe2+);
- O2-linked holo-IDO1 complex.
1.3. IDO1: Inhibitors
2. Results and Discussion
2.1. Ligand-Based Virtual Screening
2.2. Structure-Based Virtual Screening and Molecular Docking
2.3. Molecular Dynamics Simulations and Free Energy Calculation
3. Materials and Methods
3.1. IDO1
3.2. Virtual Screening
3.3. Molecular Docking
3.4. Molecular Dynamics Simulations and Free Energy Calculation
3.5. Visualization Tools and Plots
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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Compound | Docking (kcal/mol) | Compound | Docking (kcal/mol) |
---|---|---|---|
chamuvaritin | −7.9 | Kushenol C | −6.5 |
chamaejasmin B | −7.9 | butin | −6.5 |
dichamanetin | −7.8 | estrobopinin | −6.4 |
chamaejasmin | −7.7 | rhamnocitrin | −6.4 |
neochamaejasmin A | −7.6 | 7-benziloxicumarin | −6.3 |
obovatine | −7.5 | naringenin | −6.3 |
isochamanetin | −7.5 | uvaretin | −6.2 |
β-naftoflavone | −6.9 | pinocembrin | −6.1 |
pinobanksine | −6.9 | genkwanin | −6.1 |
tectocrisina | −6.8 | glabranin | −6.0 |
soforaflavanone B | −6.7 | 7-hidroxiflavanone | −6.0 |
strobopinin-7-methyl-ether | −6.7 | apigenin-4’,7-dimethyl-ether | −6.0 |
diuvaretin | −6.6 | 2-hidroxiflavanone | −6.0 |
izalpinin | −6.6 | asebogenine | −5.9 |
Kushenol E | −6.6 | steppogenin | −5.8 |
Compound | Molecular Structure | H Bond | van der Waals | Pi-Alkyl | Pi-Sigma | Pi-Pi | Alkyl | Unfavorable |
---|---|---|---|---|---|---|---|---|
chamaejasmin B | Phe185, Asn313 | Tyr15, Ile181, Gln189, Met188, Phe306, Ser309, Leu310 | Pro182, Pro314 | - | Phe185 | Lys186, Pro182 | - | |
dichamanetin | Ser12, Gly11 | Ala13, Tyr15, Lys179, Ile181, Lys186, Gln189, Phe306, Ser309, Leu310, Asn313, Pro314 | Pro182 | Pro182 | Phe185 | - | - | |
isochamanetin | Ser12, | Gly11, Ala13, Lys179, Lys186, Gln189, Asn313, Pro314 | Pro182 | Pro182 | Phe185 | - | - | |
Kushenol E | Ser12 | Gly11, Lys179, Phe185, Lys186, Gln189, Asn313, Pro314 | Pro182 | Pro182 | - | Ile181, Pro182, Phe306, Leu310 | - | |
steppogenin | Asn313 | Ser12, Tyr15, Phe185, Lys186, Phe306, Ser309, Leu310, Pro314 | Pro182 | - | - | - | Gln189 |
Energy Component | Kushenol E ΔG (kcal/mol) | Steppogenin ΔG (kcal/mol) | Dichamanetin ΔG (kcal/mol) | Isochamanetin ΔG (kcal/mol) |
---|---|---|---|---|
van der Waals | −33.4464 +/− 2.7222 | −12.6589 +/− 5.4591 | −38.7571 +/− 2.8011 | −33.1692 +/− 2.6773 |
Electrostatic | −0.4995 +/− 2.3494 | −9.5176 +/− 5.6553 | −8.1238 +/− 3.5253 | −2.7772 +/− 2.1816 |
Polar Solvation | 16.2786 +/− 3.5898 | 18.1821 +/− 8.5497 | 25.4326 +/− 4.2624 | 17.7325 +/− 2.3312 |
SASA | −3.9866 +/− 0.2390 | −1.7428 +/− 0.7148 | −4.4861 +/− 0.2483 | −3.8790 +/− 0.3585 |
Free energy of interaction | −21.6563 +/− 3.1142 | −5.7373 +/− 5.2005 | −25.9345 +/− 3.1214 | −22.0960 +/− 3.1859 |
Alloesteric Site | Kushenol E ΔG (kcal/mol) | Steppogenin ΔG (kcal/mol) | Dichamanetin ΔG (kcal/mol) | Isochamanetin ΔG (kcal/mol) |
---|---|---|---|---|
Lys179 | −5.6572 +/− 0.009 | 0.0522 +/− 0.0146 | −10.2480 +/− 0.0138 | −0.1242 +/− 0.0023 |
Ile181 | −5.5043 +/− 0.003 | −0.0478 +/− 0.0006 | −7.1328 +/− 0.0045 | −5.9646 +/− 0.0042 |
Pro182 | −2.7174 +/− 0.009 | −0.6856 +/− 0.0075 | −2.9304 +/− 0.0094 | −0.9383 +/− 0.0058 |
Phe185 | −9.7036 +/− 0.0064 | −0.1037 +/− 0.0017 | −10.9729 +/− 0.0063 | −2.6943 +/− 0.0152 |
Lys186 | −0.0069 +/− 0.0271 | −0.6023 +/− 0.0201 | −12.8116 +/− 0.0194 | −3.0506 +/− 0.0093 |
Met188 | −0.1075 +/− 0.0007 | −0.0451 +/− 0.0006 | −0.1199 +/− 0.0006 | −6.0922 +/− 0.0049 |
Gln189 | −4.2292 +/− 0.0045 | −0.0770 +/− 0.0020 | −4.7260 +/− 0.0061 | −7.7712 +/− 0.0108 |
Phe306 | −13.3145 +/− 0.0084 | −0.0055 +/− 0.0003 | −14.2844 +/− 0.0076 | −7.4103 +/− 0.0070 |
Ser309 | 0.0639 +/− 0.0090 | 0.0004 +/− 0.0012 | 0.1190 +/− 0.0077 | 2.6300 +/− 0.0092 |
Leu310 | −6.0265 +/− 0.0047 | −0.0027 +/− 0.0004 | −6.1063 +/− 0.0043 | −6.0442 +/− 0.0048 |
Asn313 | 3.2576 +/− 0.0086 | −0.0099 +/− 0.0015 | −0.0466 +/− 0.0065 | −0.0041 +/− 0.0150 |
Pro314 | −0.0440 +/− 0.0013 | −0.0007 +/− 0.0007 | −0.0231 +/− 0.0009 | −5.5250 +/− 0.0143 |
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de Almeida, V.M.; Santos-Filho, O.A. Identification of Potential Allosteric Site Binders of Indoleamine 2,3-Dioxygenase 1 from Plants: A Virtual and Molecular Dynamics Investigation. Pharmaceuticals 2022, 15, 1099. https://doi.org/10.3390/ph15091099
de Almeida VM, Santos-Filho OA. Identification of Potential Allosteric Site Binders of Indoleamine 2,3-Dioxygenase 1 from Plants: A Virtual and Molecular Dynamics Investigation. Pharmaceuticals. 2022; 15(9):1099. https://doi.org/10.3390/ph15091099
Chicago/Turabian Stylede Almeida, Vitor Martins, and Osvaldo Andrade Santos-Filho. 2022. "Identification of Potential Allosteric Site Binders of Indoleamine 2,3-Dioxygenase 1 from Plants: A Virtual and Molecular Dynamics Investigation" Pharmaceuticals 15, no. 9: 1099. https://doi.org/10.3390/ph15091099