Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Compound Design and Synthesis
2.2. Biological Activity: DNA-Binding Effects and Dihydrofolate Reductase (DHFR) Inhibition
2.3. Molecular Docking
2.4. Molecular Dynamics
3. Materials and Methods
3.1. General Information
3.2. Synthesis
Procedure for the Synthesis of Compounds 1–18
3.3. Ethidium Bromide Assay—DNA-Binding Effects
3.4. Ethidium Displacement Bromide Assay—Determination of DNA-Binding Constants
3.5. Dihydrofolate Reductase (DHFR) Inhibition Assay
3.6. Molecular Docking
3.7. Molecular Dynamics
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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No. | Decrease of Fluorescence [%] | Kapp × 105 M−1 | DHFR Affinity (kcal/mol) | DHFR IC50 (µM) | |||
---|---|---|---|---|---|---|---|
Calf Thymus DNA | T4 DNA | Poly (dA-dT)2 | poly (dG-dC)2 | ||||
EtBr | 100 | 100 | 100 | 95b* | 99 | n.d * | n.d |
1 | 74.54 | 3.0 | 1.6 | 3.1 | 3.6 | −7.5 | 21.89 ± 0.03 |
2 | 52.89 | 2.6 | 2.6 | 1.9 | 3.0 | −8.0 | 1.11 ± 0.02 |
3 | 68.85 | 1.7 | 4.1 | 4.3 | 5.3 | −7.9 | 10.13 ± 0.09 |
4 | 87.99 | 2.3 | 2.3 | 2.1 | 1.3 | −7.5 | 5.02 ± 0.03 |
5 | 72.56 | 2.7 | 1.0 | 1.3 | 2.3 | −7.9 | 30.02 ± 0.02 |
6 | 50.44 | 4.0 | 1.3 | 2.5 | 4.8 | −8.0 | 0.99 ± 0.01 |
7 | 66.89 | 4.1 | 2.1 | 3.4 | 2.3 | −7.8 | 3.02 ± 0.09 |
8 | 56.58 | 2.5 | 2.4 | 3.1 | 3.5 | −7.7 | 10.59 ± 0.06 |
9 | 64.89 | 3.9 | 1.2 | 3.9 | 1.5 | −7.6 | 56.05 ± 0.08 |
10 | 70.11 | 2.6 | 0.7 | 1.1 | 4.7 | −7.4 | 19.20 ± 0.01 |
11 | 54.54 | 1.2 | 3.1 | 2.6 | 2.5 | −7.6 | 55.32 ± 0.02 |
12 | 60.11 | 2.1 | 2.8 | 1.5 | 2.1 | −7.5 | 26.01 ± 0.02 |
13 | 49.89 | 1.9 | 2.9 | 4.0 | 3.4 | −8.0 | 0.89 ± 0.07 |
14 | 43.85 | 4.9 | 2.9 | 8.9 | 4.2 | −8.2 | 0.97 ± 0.02 |
15 | 68.82 | 1.9 | 2.3 | 3.1 | 2.4 | −7.7 | 12.01 ± 0.01 |
16 | 57.77 | 1.3 | 3.1 | 2.7 | 3.8 | −8.2 | 0.88 ± 0.02 |
17 | 41.68 | 1.8 | 2.9 | 0.5 | 2.5 | −8.1 | 1.22 ± 0.05 |
18 | 42.99 | 5.8 | 6.4 | 4.5 | 4.6 | −8.0 | 2.09 ± 0.04 |
TMP | 100 | n.d | n.d | n.d | n.d | −7.5 | 55.26 ± 0.01 |
NT [45] | 74 | 8.7 | 8.3 | 875 | 2.5 | −9.6 | 20.56 ± 0.01 |
MTX | 100 | n.d | n.d | n.d | n.d | −9.5 | 0.08 ± 0.003 |
Molecule | Residue | Type | Occupancy |
---|---|---|---|
2 | Glu-30-S * | D | 71.83% |
Glu-30-M * | D | 49.66% | |
Thr-56 | A | 47.15% | |
Ala-9 | A | 18.35% | |
Thr-136 | A | 5.52% | |
Ser-59 | A | 1.62% | |
6 | Ala-9 | A | 64.67% |
Glu-30 | D | 64.10% | |
Ser-118 | A | 29.82% | |
Phe-34 | D | 6.53% | |
Thr-56 | A | 2.33% | |
Val-115 | D | 1.10% | |
13 | Glu-30 | D | 58.02% |
Val-115 | D | 17.23% | |
Ser-118 | A | 11.47% | |
Tyr-121 | D | 1.85% | |
Ala-9 | A | 1.23% | |
14 | Glu-30 | D | 50.48% |
Ala-9 | A | 28.90% | |
Ser-118 | A | 9.35% | |
Tyr-121 | D | 1.48% | |
16 | Glu-30 | D | 33.67% |
Leu-27 | D/A | 19.65% | |
Ser-59 | D | 15.23% | |
Thr-56 | A | 7.55% | |
Ser-118 | A | 5.60% |
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Wróbel, A.; Baradyn, M.; Ratkiewicz, A.; Drozdowska, D. Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents. Int. J. Mol. Sci. 2021, 22, 3685. https://doi.org/10.3390/ijms22073685
Wróbel A, Baradyn M, Ratkiewicz A, Drozdowska D. Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents. International Journal of Molecular Sciences. 2021; 22(7):3685. https://doi.org/10.3390/ijms22073685
Chicago/Turabian StyleWróbel, Agnieszka, Maciej Baradyn, Artur Ratkiewicz, and Danuta Drozdowska. 2021. "Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents" International Journal of Molecular Sciences 22, no. 7: 3685. https://doi.org/10.3390/ijms22073685