Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone
Abstract
:1. Introduction
2. Computational Details
2.1. Structural Preparation
2.2. MD Simulations
2.3. Molecular Docking Calculations
2.4. MM/PBSA Calculations
2.5. Structure and Data Analysis
3. Results and Discussion
3.1. Structural Analysis
3.1.1. Rotenone and Annocatacin B
3.1.2. ND1—Ligand Complexes and Stability Descriptors
3.1.3. Hydrogen Bond Analysis
3.1.4. RMSF and B-Factor Analysis
3.1.5. MM Electrostatic Potential Surfaces
3.2. Binding Free Energy
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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System | Strand | Alpha Helix | 3–10 Helix | Other | Total Res. |
---|---|---|---|---|---|
ND1 | 0 (0.00%) | 154 (48.40%) | 9 (2.80%) | 155 (48.70%) | 318 |
ND1—Annocatacin B | 0 (0.00%) | 129 (39%) | 28 (8.80%) | 166 (52.20%) | 318 |
ND1—Rotenone | 0 (0.00%) | 148 (46.50%) | 11 (3.50%) | 159 (50.00%) | 318 |
ADMET | |||
---|---|---|---|
Property | Model Name | Predicted Value | |
Annocatacin B | Rotenone | ||
Absorption | Water solubility | −5.85 | −5.05 |
Absorption | Caco2 permeability | 0.40 | 1.31 |
Absorption | Intestinal absorption | 86.98 | 99.63 |
Absorption | Skin Permeability | −2.70 | −2.75 |
Absorption | P-glycoprotein substrate | Yes | No |
Absorption | P-glycoprotein I inhibitor | Yes | Yes |
Absorption | P-glycoprotein II inhibitor | Yes | Yes |
Distribution | VDss (human) e | −0.29 | −0.04 |
Distribution | Fraction unbound (human) | 0.05 | 0 |
Distribution | BBB permeability | −0.95 | −0.87 |
Distribution | CNS permeability | −2.90 | −2.82 |
Metabolism | CYP2D6 substrate | No | No |
Metabolism | CYP3A4 substrate | Yes | Yes |
Metabolism | CYP1A2 inhibitior | No | Yes |
Metabolism | CYP2C19 inhibitior | No | Yes |
Metabolism | CYP2C9 inhibitior | No | Yes |
Metabolism | CYP2D6 inhibitior | No | No |
Metabolism | CYP3A4 inhibitior | No | Yes |
Excretion | Total Clearance | 1.601 | 0.195 |
Excretion | Renal OCT2 substrate | No | No |
Toxicity | AMES toxicity | No | No |
Toxicity | Max. tolerated dose (human) | −0.64 | 0.16 |
Toxicity | hERG I inhibitor | No | No |
Toxicity | hERG II inhibitor | No | No |
Toxicity | Oral Rat Acute Toxicity (LD50) | 3.03 | 2.87 |
Toxicity | Oral Rat Chronic Toxicity (LOAEL) | 0.79 | 1.43 |
Toxicity | Hepatotoxicity | No | No |
Toxicity | Skin Sensitisation | No | No |
Toxicity | T.Pyriformis toxicity | 0.31 | 0.35 |
Toxicity | Minnow toxicity | −1.89 | −0.33 |
System | Region | RMSD | RMSF | RG | H B | ||
---|---|---|---|---|---|---|---|
Intra | Inter/Solv | Inter/Mem | |||||
ND1 | whole prot | 0.40 ± 0.02 | 0.19 ± 0.09 | 2.12 ± 0.01 | 209 ± 9 (200) | 338 ± 15 (336) | 33 ± 5 (39) |
Active site | 0.30 ± 0.05 | 0.13 ± 0.04 | 1.91 ± 0.01 | 89 ± 6 (77) | 166 ± 10 (165) | 6 ± 2 (6) | |
y-axis | 1.74 ± 0.03 | ||||||
ND1 + rotenone | whole prot | 0.48 ± 0.02 | 0.20 ± 0.10 | 2.13 ± 0.01 | 203 ± 8 (202) | 356 ± 13 (356) | 31 ± 5 (38) |
Active site | 0.41 ± 0.11 | 0.14 ± 0.07 | 1.90 ± 0.02 | 84 ± 6 (88) | 176 ± 10 (174) | 8 ± 3 (10) | |
y-axis | 1.70 ± 0.04 | ||||||
ND1 + annocatacin B | whole prot | 0.44 ± 0.01 | 0.20 ± 0.09 | 2.13 ± 0.01 | 213 ± 11 (207) | 341 ± 14 (330) | 26 ± 5 (23) |
Active site | 0.30 ± 0.03 | 0.13 ± 0.05 | 1.90 ± 0.01 | 89 ± 6 (81) | 167 ± 10 (161) | 5 ± 3 (2) | |
y-axis | 1.77 ± 0.02 |
System | Active Site | Other Sites | |||||
---|---|---|---|---|---|---|---|
Site A | Site B | ||||||
ND1 + rot + mem | T73(21) | A74(19) | L77(37) | ||||
L22(23) | F223(144) | A78(15) | L79(45) | I81(20) | |||
A226(14) | T229(17) | A82(18) | L83(37) | L85(19) | |||
N230(36) | I232(10) | W86(68) | L89(30) | M91(23) | |||
M233(20) | S115(23) | I116(38) | W118(41) | ||||
S119(37) | |||||||
ND1 + ann + mem | L222(94) | F223(103) | A78(102) | L79(179) | I81(101) | ||
E143(39) | L146(27) | F224(106) | M225(232) | A82(76) | L85(43) | S109(48) | |
W185(14) | F186(41) | A226(70) | E227(48) | A112(40) | V113(53) | Y114(52) | |
S188(13) | T189(14) | T229(27) | N230(25) | S115(39) | I116(70) | L117(74) | |
A191(14) | E192(15) | I231(37) | M233(49) | L266(28) | T267(19) | L269(46) | |
M234(36) | L237(50) | F270(26) | I273(49) |
System | |||||
---|---|---|---|---|---|
ND1-Annocatacin B | −358.76 ± 1.26 | −23.04 ± 0.69 | 85.00 ± 0.92 | −36.38 ± 0.10 | −333.18 ± 2.14 |
ND1-Rotenone | −219.81 ± 0.89 | −21.14 ± 0.39 | 45.01 ± 0.34 | −22.21 ± 0.06 | −218.15 ± 1.78 |
ND1—Rotetone | ||||
---|---|---|---|---|
A226 | −8.18 ± 0.12 | 0.92 ± 0.06 | −12.27 ± 0.19 | −19.53 ± 0.24 |
F223 | −14.37 ± 0.20 | 3.94 ± 0.08 | 1.06 ± 0.63 | −9.41 ± 0.60 |
I81 | −9.21 ± 0.11 | 0.66 ± 0.02 | 4.19 ± 0.14 | −4.36 ± 0.19 |
T229 | −4.32 ± 0.11 | 5.20 ± 0.13 | −5.06 ± 0.32 | −4.17 ± 0.35 |
L85 | −5.97 ± 0.11 | 0.72 ± 0.07 | 1.10 ± 0.13 | −4.15 ± 0.16 |
N230 | −1.35 ± 0.06 | 0.72 ± 0.06 | −2.86 ± 0.14 | −3.49 ± 0.16 |
L222 | −9.03 ± 0.10 | 2.46 ± 0.07 | 3.79 ± 0.18 | −2.77 ± 0.22 |
M225 | −3.74 ± 0.13 | 1.19 ± 0.07 | 0.24 ± 0.12 | −2.31 ± 0.13 |
M233 | −2.77 ± 0.07 | 2.23 ± 0.07 | −1.51 ± 0.11 | −2.05 ± 0.13 |
E192 | −1.61 ± 0.08 | −0.17 ± 0.15 | −0.22 ± 0.01 | −2.00 ± 0.16 |
ND1—Annocatacin B | ||||
V113 | −12.39 ± 0.22 | 2.74 ± 0.12 | −5.20 ± 0.34 | −14.84 ± 0.54 |
M234 | −10.30 ± 0.16 | 3.67 ± 0.08 | −2.80 ± 0.16 | −9.43 ± 0.24 |
N230 | −10.59 ± 0.19 | 6.10 ± 0.13 | −3.82 ± 0.17 | −8.30 ± 0.25 |
A226 | −4.94 ± 0.22 | 0.60 ± 0.08 | −2.59 ± 0.46 | −6.92 ± 0.61 |
E192 | −8.48 ± 0.20 | 1.29 ± 0.35 | 1.11 ± 0.22 | −6.09 ± 0.33 |
I231 | −4.26 ± 0.10 | −0.19 ± 0.02 | −0.74 ± 0.09 | −5.19 ± 0.13 |
E227 | −0.98 ± 0.26 | −3.77 ± 0.29 | −0.35 ± 0.10 | −5.09 ± 0.30 |
M233 | 9.20 ± 0.16 | 4.13 ± 0.08 | 0.61 ± 0.09 | −4.46 ± 0.18 |
L237 | −6.74 ± 0.20 | 1.18 ± 0.03 | 1.15 ± 0.07 | −4.40 ± 0.19 |
F270 | −7.34 ± 0.16 | 1.39 ± 0.06 | 2.06 ± 0.10 | −3.90 ± 0.15 |
ND1—Rotetone | ||||
---|---|---|---|---|
W118 | −7.31 ± 0.12 | 2.65 ± 0.07 | 13.05 ± 0.30 | 8.39 ± 0.30 |
S119 | −1.11 ± 0.04 | 1.12 ± 0.07 | 6.11 ± 0.23 | 6.12 ± 0.22 |
S115 | −4.37 ± 0.11 | 1.67 ± 0.06 | 7.78 ± 0.20 | 5.09 ± 0.20 |
W86 | −4.52 ± 0.10 | 0.93 ± 0.05 | 5.21 ± 0.25 | 1.61 ± 0.25 |
K262 | 1.14 ± 0.01 | −0.13 ± 0.01 | 0.22 ± 0.00 | 1.23 ± 0.01 |
R195 | 1.61 ± 0.03 | −0.58 ± 0.04 | 0.00 ± 0.00 | 1.03 ± 0.05 |
E214 | 1.53 ± 0.03 | −0.75 ± 0.02 | 0.07 ± 0.00 | 0.85 ± 0.02 |
Y215 | −0.47 ± 0.02 | 0.41 ± 0.03 | 0.91 ± 0.12 | 0.84 ± 0.13 |
A78 | −9.30 ± 0.11 | 2.64 ± 0.06 | 7.37 ± 0.23 | 0.71 ± 0.29 |
E59 | 1.05 ± 0.02 | −0.30 ± 0.01 | −0.17 ± 0.00 | 0.58 ± 0.01 |
ND1—Annocatacin B | ||||
I116 | −3.78 ± 0.09 | 0.51 ± 0.03 | 11.40 ± 0.24 | 8.14 ± 0.23 |
F223 | −4.83 ± 0.13 | 2.67 ± 0.15 | 7.50 ± 0.25 | 5.35 ± 0.30 |
E143 | −7.08 ± 0.23 | 8.98 ± 0.56 | 0.70 ± 0.10 | 2.65 ± 0.52 |
A78 | −3.20 ± 0.08 | 2.23 ± 0.09 | 3.42 ± 0.15 | 2.44 ± 0.16 |
R274 | −1.97 ± 0.13 | 4.04 ± 0.10 | −0.08 ± 0.01 | 1.98 ± 0.13 |
S109 | −5.27 ± 0.17 | 5.55 ± 0.15 | 1.55 ± 0.10 | 1.82 ± 0.21 |
R134 | 1.12 ± 0.02 | 0.65 ± 0.03 | −0.16 ± 0.00 | 1.61 ± 0.04 |
R195 | 0.83 ± 0.04 | 0.74 ± 0.03 | 0.01 ± 0.00 | 1.59 ± 0.04 |
R34 | −0.24 ± 0.06 | 1.88 ± 0.06 | −0.08 ± 0.00 | 1.55 ± 0.08 |
S188 | −6.55 ± 0.12 | 6.38 ± 0.14 | 1.72 ± 0.09 | 1.55 ± 0.19 |
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Febres-Molina, C.; Aguilar-Pineda, J.A.; Gamero-Begazo, P.L.; Barazorda-Ccahuana, H.L.; Valencia, D.E.; Vera-López, K.J.; Davila-Del-Carpio, G.; Gómez, B. Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone. Polymers 2021, 13, 1840. https://doi.org/10.3390/polym13111840
Febres-Molina C, Aguilar-Pineda JA, Gamero-Begazo PL, Barazorda-Ccahuana HL, Valencia DE, Vera-López KJ, Davila-Del-Carpio G, Gómez B. Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone. Polymers. 2021; 13(11):1840. https://doi.org/10.3390/polym13111840
Chicago/Turabian StyleFebres-Molina, Camilo, Jorge A. Aguilar-Pineda, Pamela L. Gamero-Begazo, Haruna L. Barazorda-Ccahuana, Diego E. Valencia, Karin J. Vera-López, Gonzalo Davila-Del-Carpio, and Badhin Gómez. 2021. "Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone" Polymers 13, no. 11: 1840. https://doi.org/10.3390/polym13111840