Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight
Abstract
:1. Introduction
2. Results and Discussion
2.1. Investigation of FRα Binding Site
2.2. Molecular Docking
2.3. Molecular Dynamics (MD) Simulation
2.3.1. Root Mean Square Deviation (RMSD) Analysis
2.3.2. Root Mean Square Fluctuation (RMSF) Analysis
2.3.3. Binding Free Energy Calculation by Molecular Mechanics–Poisson-Boltzmann Surface Accessible (MM-PBSA)
2.3.4. Hydrogen Bond Properties
2.3.5. Pocket Volume Calculations
2.3.6. General Effects of the Binding of FOL03 and FOL08 Inside FRα
2.4. ADMET Prediction
3. Materials and Methods
3.1. Determination of the Size of the Binding Site
3.2. Molecular Docking
3.3. Molecular Dynamics (MD) Simulation
3.4. Free Binding Energy Calculation by MM-PBSA
3.5. Pocket Volume (POVME) Algorithm
3.6. ADMET Prediction
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Compound | FBE (kcal/mol) | Ki (Picomolar pM) |
---|---|---|
FA | −13.20 | 209.24 |
MTX | −11.87 | 2000 |
PTX | −14.05 | 37.88 |
FOL01 | −15.71 | 3.060 |
FOL02 | −15.79 | 2.67 |
FOL03 | −16.83 | 0.460 |
FOL04 | −15.84 | 2.440 |
FOL05 | −15.86 | 2.39 |
FOL06 | −15.88 | 2.28 |
FOL07 | −15.64 | 3.41 |
FOL08 | −16.24 | 1.48 |
FOL09 | −14.34 | 30.88 |
FOL10 | −15.56 | 3.92 |
FOL11 | −14.40 | 27.68 |
FOL12 | −13.84 | 71.24 |
FOL13 | −14.75 | 15.40 |
FOL14 | −14.87 | 12.49 |
FOL15 | −15.71 | 3.06 |
FOL16 | −14.82 | 13.73 |
FOL17 | −15.24 | 6.74 |
FOL18 | −14.81 | 13.84 |
FOL19 | −14.98 | 10.43 |
Complex with FRα | kcal/mol | VDWLS kcal/mol | EEL kcal/mol | Gpolar kcal/mol | Gnon-polar kcal/mol | AutoDock kcal/mol |
---|---|---|---|---|---|---|
FA | −59.59 ± 0.17 | −55.84 ± 0.15 | −91.97 ± 0.28 | 94.35 ± 0.21 | −6.12 ± 0.01 | −13.20 |
MTX | −45.12 ± 0.18 | −60.71 ± 0.12 | −48.05 ± 0.39 | 69.98 ± 0.31 | −6.34 ± 0.01 | −11.87 |
PTX | −30.11 ± 0.36 | −41.38 ± 0.24 | −44.14 ± 0.48 | 60.57 ± 0.40 | −5.16 ± 0.03 | −14.05 |
FOL03 | −73.62 ± 0.21 | −61.47 ± 0.13 | −134.73 ± 0.40 | 129.16 ± 0.28 | −6.58 ± 0.01 | −16.83 |
FOL08 | −79.68 ± 0.21 | −75.96 ± 0.15 | −99.95 ± 0.38 | 104.81 ± 0.27 | −8.57 ± 0.01 | −16.24 |
Code | H-Bond Acceptor (atom@res) | H-Bond Donor (atom@H) | Donor (atom@res) | H-Bond Occupancy (%) | Average Distance (Å) | Average Angle (°) |
---|---|---|---|---|---|---|
FA | ||||||
ASP81@OD1 | FA@H2 | FA@N3 | 61.28 | 2.83 | 159.70 | |
ASP81@OD2 | FA@H4 | FA@N5 | 56.09 | 2.79 | 163.65 | |
ASP81@OD2 | FA@H3 | FA@N5 | 16.67 | 2.79 | 163.66 | |
ASP81@OD1 | FA@H3 | FA@N5 | 13.01 | 2.81 | 161.64 | |
ASP81@OD2 | FA@H2 | FA@N3 | 11.26 | 2.85 | 152.98 | |
FA@O | ARG103@HH12 | ARG103@NH1 | 17.18 | 2.84 | 149.17 | |
HIS135@O | FA@H6 | FA@O3 | 56.89 | 2.72 | 156.37 | |
FA@N1 | HIS135@HE2 | HIS135@NE2 | 21.31 | 2.92 | 162.11 | |
FA@O1 | TRP140@HE1 | TRP140@NE1 | 43.77 | 2.83 | 148.12 | |
MTX | ||||||
ASP81@OD1 | MTX@H3 | MTX@N5 | 22.89 | 2.82 | 152.41 | |
ASP81@OD1 | MTX@H | MTX@N5 | 22.15 | 2.81 | 153.59 | |
ASP81@OD2 | MTX@H | MTX@N5 | 13.03 | 2.83 | 153.19 | |
MTX@N4 | ARG103@HH12 | ARG103@NH1 | 10.22 | 2.91 | 147.23 | |
MTX@N4 | HIS135@HE2 | HIS135@NE2 | 10.96 | 2.91 | 158.30 | |
PTX | ||||||
ASP81@OD1 | PTX@H4 | PTX@N3 | 11.46 | 2.81 | 159.08 | |
PTX@O | HIS135@HE2 | HIS135@NE2 | 45.99 | 2.84 | 160.57 | |
HIS135@O | PTX@H6 | PTX@N4 | 20.06 | 2.86 | 153.34 | |
FOL03 | ||||||
ASP81@OD2 | FOL03@H5 | FOL03@N5 | 75.40 | 2.82 | 157.41 | |
ASP81@OD2 | FOL03@H3 | FOL03@N3 | 74.93 | 2.76 | 151.43 | |
ASP81@OD1 | FOL03@H4 | FOL03@N7 | 70.12 | 2.76 | 148.54 | |
ASP81@OD1 | FOL03@H5 | FOL03@N5 | 28.07 | 2.86 | 147.80 | |
TYR60@O | FOL03@H6 | FOL03@N10 | 23.44 | 2.89 | 157.28 | |
FOL03@O4 | ARG61@HE | ARG61@NE | 18.90 | 2.86 | 157.00 | |
FOL03@O5 | ARG61@HH21 | ARG61@NH2 | 16.70 | 2.88 | 157.43 | |
FOL03@O FOL03@O FOL03@N2 | ARG107@HH11 ARG107@HH21 ARG107@HH21 | ARG107@NH1 ARG107@NH2 ARG107@NH2 | 26.63 18.56 13.63 | 2.84 2.85 2.92 | 149.99 147.16 156.63 | |
FOL08 | ||||||
ASP81@OD1 | FOL08@H3 | FOL08@N4 | 63.39 | 2.79 | 163.29 | |
ASP81@OD2 | FOL08@H | FOL08@N2 | 44.73 | 2.83 | 152.71 | |
ASP81@OD1 | FOL08@H | FOL08@N2 | 41.74 | 2.83 | 150.17 | |
ASP81@OD2 | FOL08@H3 | FOL08@N4 | 32.20 | 2.77 | 162.82 | |
FOL08@O4 | ARG61@HH21 | ARG61@NH2 | 15.71 | 2.84 | 158.32 | |
HIS135@O | FOL08@H6 | FOL08@O3 | 33.81 | 2.71 | 158.35 | |
FOL08@N | HIS135@HE2 | HIS135@NE2 | 18.73 | 2.92 | 160.57 | |
FOL08@O2 | TRP140@HE1 | TRP140@NE1 | 16.08 | 2.86 | 156.43 | |
FOL08@N1 | SER174@HG | SER174@OG | 32.52 | 2.89 | 164.20 | |
FOL08@O | SER174@HG | SER174@OG | 10.11 | 2.80 | 155.58 |
Property | Model Name | Predicted Value | ||||
---|---|---|---|---|---|---|
FA | MTX | PTX | FOL03 | FOL08 | ||
Absorption | Water solubility (log mol/L) | −2.88 | −2.859 | −2.842 | −2.892 | −2.905 |
Caco2 permeability (log cm/s) | −0.877 | −0.77 | −0.954 | −0.92 | −0.667 | |
Human intestinal absorption (% absorbed) | 17.745 | 35.716 | 37.981 | 7.719 | 76.253 | |
Skin permeability (log Kp) | −2.735 | −2.735 | −2.735 | −2.735 | −2.735 | |
P-glycoprotein substrate | Yes | Yes | Yes | Yes | Yes | |
P-glycoprotein I inhibitor | No | No | No | No | No | |
P-glycoprotein II inhibitor | No | No | No | No | No | |
Distribution | Human volume of distribution (log L/kg) | 0.046 | −0.883 | −0.927 | −0.548 | −0.720 |
Human fraction unbound (Fu) | 0.370 | 0.183 | 0.160 | 0.276 | 0.127 | |
Blood Brain Barrier (BBB)permeability (log BB) | −1.615 | −1.865 | −1.442 | −3.458 | −2.372 | |
CNS permeability (log PS) | −4.262 | −3.818 | −4.022 | −7.265 | −4.174 | |
Metabolism | CYP2D6 substrate | No | No | No | No | No |
CYP3A4 substrate | No | No | No | No | No | |
CYP1A2 inhibitor | No | No | No | No | No | |
CYP2C19 inhibitor | No | No | No | No | No | |
CYP2C9 inhibitor | No | No | No | No | No | |
CYP2D6 inhibitor | No | No | No | No | No | |
CYP3A4 inhibitor | No | No | No | No | No | |
Excretion | Total clearance (log ml/min/kg) | 0.527 | 0.378 | 0.285 | −0.196 | −0.111 |
Renal OCT2 substrate | No | No | No | No | No | |
Toxicity | Ames toxicity | No | No | No | No | No |
Max. human tolerated dose (log mg/kg/day) | −0.586 | −0.827 | −0.292 | 0.366 | 0.489 | |
hERG I inhibitor | No | No | No | No | No | |
hERG II inhibitor | No | Yes | No | No | No | |
Oral rat acute toxicity (LD50) (mol/kg) | 2.670 | 2.713 | 2.585 | 2.483 | 2.501 | |
Oral rat chronic toxicity (LOAEL) (log mg/kg_bw/day) | 3.153 | 3.112 | 3.111 | 4.876 | 3.152 | |
Skin sensitization | No | No | No | No | No | |
T. pyriformis toxicity (log ug/L) | 0.285 | 0.285 | 0.285 | 0.285 | 0.285 | |
Minnow toxicity (log mM) | 4.009 | 2.384 | 2.867 | 4.886 | 1.221 |
System | Total Numberof Atoms | Number of Heteroatoms | Water Atoms | Neutralizing Atoms |
---|---|---|---|---|
FRα + FA | 29,808 | 3634 | 9033 | 3 Cl− |
FRα + MTX | 29,812 | 3639 | 9033 | 3 Cl− |
FRα + PTX | 29,808 | 3643 | 9033 | 3 Cl− |
FRα + FOL03 | 29,807 | 3635 | 9031 | 3 Cl− |
FRα + FOL08 | 29,809 | 3643 | 9029 | 3 Cl− |
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Al-Thiabat, M.G.; Saqallah, F.G.; Gazzali, A.M.; Mohtar, N.; Yap, B.K.; Choong, Y.S.; Wahab, H.A. Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight. Molecules 2021, 26, 1079. https://doi.org/10.3390/molecules26041079
Al-Thiabat MG, Saqallah FG, Gazzali AM, Mohtar N, Yap BK, Choong YS, Wahab HA. Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight. Molecules. 2021; 26(4):1079. https://doi.org/10.3390/molecules26041079
Chicago/Turabian StyleAl-Thiabat, Mohammad G., Fadi G. Saqallah, Amirah Mohd Gazzali, Noratiqah Mohtar, Beow Keat Yap, Yee Siew Choong, and Habibah A Wahab. 2021. "Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight" Molecules 26, no. 4: 1079. https://doi.org/10.3390/molecules26041079