Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors
Abstract
:1. Introduction
2. Results
2.1. Data Mining of PKIs
2.2. Chemoinformatic Analysis of PKIs
2.2.1. Molecular Descriptors
2.2.2. Relationship between Aromatic Rings and Hydrogen Bonds
2.3. Aromatic Rings as Determinants for Molecular Recognition of PKIs
2.3.1. Modes of Non-Bonded Intermolecular Interactions
2.3.2. Strengths of Non-Bonded Intermolecular Interactions
3. Discussions
4. Theory and Methods
4.1. Data Mining of PKIs
- The 28 March 2018 release of the PDB was searched for Pfam [35] accession numbers PF00069, PF07714, PF00454, PF00794 and PF12330, resulting in a total of 4884 entries that contained protein kinases;
- Only high-resolution (2.5 Å or better) X-ray crystal structures of protein kinases complexed with bound PKIs were retained for further analysis. The reason for the cut-off is two-fold: (i) to ensure quality of the structures, and (ii) to ensure that selected PKIs have a sufficiently high binding affinity to kinase because the formation of a well-ordered ligand-protein co-crystal that is good enough for 2.5 Å resolution requires a reasonably high binding affinity [60];
- Multiple protein kinases bound with the same PKI were filtered out to retain one protein kinase only for each PKI.
4.2. Chemoinformatic Analysis: Molecular Descriptors
4.3. Quantum Chemical Calculation of Intermolecular Interaction Energies
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Name | Description |
---|---|
MW | Molecular weight |
nHDon | Number of donor atoms for hydrogen bond (HB) |
nHAcc | Number of acceptor atoms for HB |
SA | Total surface area |
TPSA | Topological polar surface area |
nSK | Number of non-H atoms |
nsp3 | Number of sp3 hybridized carbon atoms |
RBN | Number of rotatable bonds |
ARR | Aromatic ratio |
cLogP | Calculated partition coefficient between octanol and water |
nAR | Number of aromatic rings |
Fsp3 | Fraction of sp3 carbon atoms |
Molecular Descriptor | Min | Median | Max | Average | Ro5 a | Veber b |
---|---|---|---|---|---|---|
MW (Da) | 94.12 | 390.29 | 1057.11 | 390.76 ± 2.28 | 85.4% | - |
nHDon | 0 | 2 | 16 | 2.21 ± 0.03 | 99.2% | 83.5% c |
nHAcc | 1 | 7 | 27 | 6.77 ± 0.05 | 96.6% | |
cLogP | −5.95 | 2.58 | 7.94 | 2.60 ± 0.03 | 94.1% | - |
SA (Å2) | 77.39 | 289.53 | 761.02 | 289.47 ± 1.69 | - | - |
TPSA (Å2) | 16.61 | 94.06 | 457.72 | 95.64 ± 0.72 | - | 92.9% |
RBN | 0 | 5 | 32 | 4.77 ± 0.06 | - | 96.7% |
ARR | 0 | 0.58 | 1 | 0.59 ± 0.00 | - | - |
nAR | 0 | 3 | 8 | 3.04 ± 0.02 | - | - |
Nsp3 | 0 | 6 | 31 | 6.38 ± 0.09 | - | - |
nSK | 7 | 28 | 74 | 27.81 ± 0.17 | - | - |
Fsp3 | 0 | 0.30 | 1.36 | 0.31 ± 0.00 | - | - |
Number of Aromatic Rings | Number of PKIs | Percentage (%) | Average of WHBC |
---|---|---|---|
0 | 1 | 0.05 | 0.474 ± 0 |
1 | 117 | 5.47 | 0.381 ± 0.013 |
2 | 507 | 23.70 | 0.369 ± 0.005 |
3 | 819 | 38.29 | 0.326 ± 0.003 |
4 | 570 | 26.65 | 0.296 ± 0.003 |
5 and more | 125 | 5.84 | 0.293 ± 0.004 |
Residue | Interaction Mode | |||
---|---|---|---|---|
Met477 | H-bond, CH–π | −4.1 | 3.8 | −0.3 |
Lys481 | H-bond | −3.6 | 3.3 | −0.3 |
Tyr476 | π–π, CH–π | −4.0 | 2.5 | −1.5 |
Phe540 | π–π, NH–π | −2.8 | 0.4 | −2.4 |
Lys430 | cation–π, NH–π, CH–π | −12.8 | 5.4 | −7.3 |
Val416 | CH–π | −3.0 | 0.1 | −2.9 |
Ala428 | CH–π | −1.5 | -0.1 | −1.6 |
Val458 | CH–π | −1.2 | -0.1 | −1.3 |
Ile472 | CH–π | −1.4 | 0.0 | −1.4 |
Leu528 | CH–π | −3.9 | 1.2 | −2.7 |
Leu542 | CH–π | −1.4 | 0.0 | −1.4 |
Table | Residue | Interaction Mode | Combined Energy (kcal/mol) | |
---|---|---|---|---|
Hydrogen Bonding | Met477 | H-bond, CH–π | −0.3 | −0.6 |
Lys481 | H-bond | −0.3 | ||
non-bonded π-interactions | Tyr476 | π–π, CH–π | −1.5 | −22.5 |
Phe540 | π–π, NH–π | −2.4 | ||
Lys430 | cation–π, NH–π, CH–π | −7.3 | ||
Val416 | CH–π | −2.9 | ||
Ala428 | CH–π | −1.6 | ||
Val458 | CH–π | −1.3 | ||
Ile472 | CH–π | −1.4 | ||
Leu528 | CH–π | −2.7 | ||
Leu542 | CH–π | −1.4 |
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Zhu, Y.; Alqahtani, S.; Hu, X. Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors. Molecules 2021, 26, 1776. https://doi.org/10.3390/molecules26061776
Zhu Y, Alqahtani S, Hu X. Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors. Molecules. 2021; 26(6):1776. https://doi.org/10.3390/molecules26061776
Chicago/Turabian StyleZhu, Yan, Saad Alqahtani, and Xiche Hu. 2021. "Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors" Molecules 26, no. 6: 1776. https://doi.org/10.3390/molecules26061776
APA StyleZhu, Y., Alqahtani, S., & Hu, X. (2021). Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors. Molecules, 26(6), 1776. https://doi.org/10.3390/molecules26061776