In Silico Approach to Design of New Multi-Targeted Inhibitors Based on Quinoline Ring with Potential Anticancer Properties
Abstract
:1. Introduction
2. Results and Discussion
2.1. Designing Strategy
2.1.1. Molecular Targets
2.1.2. Reference Compounds
2.1.3. Designed Compounds
2.2. Binding Properties of Designed Compounds Based on Molecular Docking
2.3. Molecular Dynamics Simulation Results
2.4. ADMET Properties of the Tested Compounds
3. Materials and Methods
3.1. Molecular Docking
3.2. Molecular Dynamics Simulation Details
3.3. ADMET Evaluation
4. Conclusions and Summary
- -
- All designed compounds bind to the active site of the three tested proteins with negative binding affinity;
- -
- Molecular dynamics simulation confirmed the stability of the formed complexes, and the calculated binding free energies for all derivatives were found to be negative (Table 7);
- -
- Reducing the size of the molecule does not affect key structural elements that determine binding to selected molecular targets;
- -
- The introduced modifications had a positive impact on the ADMET parameter profile (Table 9);
- -
- -
- Potential disadvantages, such as a short biological half life or effects on metabolic enzymes, can be overcome, for example, by developing a suitable formulation of the new drug.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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M0 | M1 | M2 | M3 | M4 | M5 | M6 | |
---|---|---|---|---|---|---|---|
van der Waals interactions | DG A:12 ARG C:488 PTR C:723 ASN C:722 THR C:718 | ARG C:488 PTR C:723 ASN C:722 ILE C:535 | ARG C:364 DG A:12 ARG C:488 PTR C:723 THR C:718 ASP C:533 ILE C:535 | ARG C:364 DG A:12 ARG C:488 ASN C:722 THR C:718 LYS C:452 | ARG C:364 DG A:12 ARG C:488 PTR C:723 ASN C:722 THR C:718 | ARG C:364 DG A:12 ARG C:488 PTR C:723 ASN C:722 THR C:718 | ARG C:364 DG A:12 ARG C:488 PTR C:723 ASN C:722 THR C:718 HIS C:632 |
Hydrogen bonds | ARG C:364 LYS C:532 GLU C:356 ASP C:533 | DG A:11 ARG C:364 THR C:718 | DG A:11 DA B:113 LYS C:532 | DG A:11 DA B:113 LYS C:532 | DG A:11 LYS C:532 | DG A:11 LYS C:532 | DG A:11 DA B:113 LYS C:532 |
Carbon–hydrogen interactions | DT A:10 | DG A:11 ASP C:533 HIS C:632 DG A:12 | DT A:10 | DT A:10 DG A:11 | DT A:10 DG A:11 ASN C:532 | DT A:10 DG A:11 ASP C:533 | DT A:10 DG A:11 |
π-type interactions | DA B:113 DG A:11 DC B:112 | DT A:10 DG A:11 DA B:113 DC B:112 | DT A:10 DG A:11 DA B:113 DC B:112 | DT A:10 DG A:11 DA B:113 DC B:112 | DG A:11 DA B:113 DC B:112 DT A:10 | DT A:10 DG A:11 DA B:113 DC B:112 | DT A:10 DG A:11 DA B:113 DC B:112 |
Alkyl/π–alkyl interactions | DG A:11 | DA B:113 | DT A:10 DG A:11 DA B:113 | DT A:10 | DT A:10 | DT A:10 | DT A:10 DA B:113 |
M7 | M8 | M9 | M10 | M11 | M12 | |
---|---|---|---|---|---|---|
van der Waals interactions | ARG C:364 DG A:12 ARG C:488 PTR C:723 ASN C:722 THR C:718 LYS C:532 | ARG C:364 DG A:12 ARG C:488 PTR C:723 ASN C:722 THR C:718 ASP C:533 HIS C:632 | DG A:12 ARG C:488 PTR C:723 ASN C:722 THR C:718 | ARG C:364 DG A:12 ARG C:488 PTR C:723 ASN C:722 THR C:718 ASP C:533 | ARG C:488 ASN C:722 THR C:718 | ARG C:488 PTR C:723 ASN C:722 THR C:718 ASP C:533 ASN C:532 GLU C:356 |
Hydrogen bonds | DG A:11 DA B:113 | DG A:11 DA B:113 LYS C:532 | DG A:11 LYS C:532 LYS C:751 DT A:10 | DG A:11 LYS C:532 | ARG C:364 LYS C:532 | DG A:11 LYS C:532 |
Carbon–hydrogen interactions | DT A:10 ASP C:533 | DT A:10 DG A:11 GLU C:356 | ASP C:533 DA B:113 DA B:114 | DT A:10 | PTR C:723 | DT A:10 DG A:11 |
π-type interactions | DG A:11 DA B:113 DC B:112 | DT A:10 DG A:11 DA B:113 DC B:112 | DT A:11 DT A:10 | DG A:11 DA B:113 DC B:112 | DA B:113 DG A:11 DC B:112 | DA B:113 DG A:11 DC B:112 |
π–alkyl/alkyl | DT A:10 DA B:113 | DT A:10 DA B:113 | LEU C:721 | DT A:10 DA B:113 | DT A:10 DG A:11 DA B:113 | DT A:10 DA B:113 |
M0 | M1 | M2 | M3 | M4 | M5 | M6 | |
---|---|---|---|---|---|---|---|
van der Waals interactions | ASP A:88 ASP A:144 | TRP A:81 LYS A:91 ASP A:88 GLN A:85 PRO A:86 LEU A:96 PHE A:83 TYR A:139 CYS A:136 | TRP A:81 GLN A:85 PRO A:86 PHE A:83 TYR A:139 LEU A:94 ASN A:140 | TRP A:81 PHE A:83 TYR A:139 LEU A:94 ASN A:140 TYR A:97 ASN A:135 LEU A:92 ASP A:144 | PRO A:86 PHE A:83 TYR A:139 CYS A:136 TYR A:97 | ASP A:88 GLN A:85 PRO A:86 PHE A:83 TYR A:139 ASN A:140 ASN A:135 | TRP A:81 PHE A:83 TYR A:139 LEU A:94 TYR A:97 LEU A:92 ASP A:144 |
Hydrogen bond | ASP A:145 GLN A:85 TRP A:81 | PRO A: 82 ASN A:140 | ASP A:88 TYR A:97 | ILE A:146 ASP A:145 | PRO A:82 ASN A:140 | TYR A:97 | |
Carbon–hydrogen interactions | VAL A:87 | ASN A:140 | ASN A:135 | PRO A:82 GLN A:85 | MET A:132 | ||
π-type interactions | PRO A:86 ILE A:146 | LEU A:92 ILE A:146 | ILE A:146 | LEU A:92 | ILE A:146 | LEU A:92 ILE A:146 | ILE A:146 |
π–alkyl/alkyl | LEU A:92 | VAL A:87 TYR A:97 LEU A:92 | LEU A:92 VAL A:87 CYS A:136 PRO A:82 | VAL A:87 CYS A:136 PRO A:82 | VAL A:87 PRO A:82 TRP A:81 | VAL A:87 CYS A:136 PRO A:82 TRP A:81 | VAL A:87 CYS A:136 PRO A:82 |
M7 | M8 | M9 | M10 | M11 | M12 | |
---|---|---|---|---|---|---|
van der Waals interactions | TRP A:81 PHE A:83 TYR A:139 LEU A:94 TYR A:97 LEU A:92 ASP A:144 | ASP A:88 GLN A:85 PRO A:86 PHE A:83 TYR A:139 ASN A:140 | ASP A:88 GLN A:85 PRO A:86 PHE A:83 TYR A:139 LEU A:94 TYR A:97 | ASP A:88 PRO A:86 PHE A:83 TYR A:139 ASN A:140 MET A:132 TRP A:81 | ASP A:88 TYR A:139 ASN A:140 ASN A:135 LEU A:92 | PRO A:86 PHE A:83 TYR A:139 LEU A:94 ASN A:140 GLN A:84 |
Hydrogen bonds | ASN A:140 ASP A:145 | TYR A:97 | PRO A:82 TYR A:97 | GLN A:85 | ASP A:88 TYR A:97 TRP A:81 | |
Carbon–hydrogen interactions | ASN A:135 MET A:132 TRP A:81 | ASN A:140 VAL A:87 | ASN A:135 GLN A:85 | TRP A:81 TYR A:97 PRO A:86 | ASN A:135 | |
π-type interactions | ILE A:146 | PHE A:83 CYS A:136 | LEU A:92 | |||
π–alkyl/alkyl | ILE A:146 VAL A:87 CYS A:136 PRO A:82 | ILE A:146 LEU A:92 VAL A:87 CYS A:136 PRO A:82 TRP A:81 | ILE A:146 LEU A:92 VAL A:87 CYS A:136 PRO A:82 TRP A:81 | ILE A:146 LEU A:92 VAL A:87 CYS A:136 PRO A:82 | ILE A:146 VAL A:87 CYS A:136 PRO A:82 | ILE A:146 VAL A:87 CYS A:136 PRO A:82 |
M0 | M1 | M2 | M3 | M4 | M5 | M6 | |
---|---|---|---|---|---|---|---|
van der Waals interactions | THR B:435 SER A:440 PHE A:432 SER B:440 THR B:542 ASN A:436 MET B:549 | LEU B:405 PHE B:432 THR B:435 SER A:440 THR A:435 PHE A:432 SER B:440 | LEU B:405 PHE B:432 THR B:435 SER A:440 THR A:435 PHE A:432 SER B:440 ASN B:436 | PHE B:432 THR B:435 SER A:440 THR A:435 PHE A::432 SER B:440 THR B:542 ILE B:543 | PHE B:432 THR B:435 SER A:440 THR A:435 PHE A:432 SER B:440 | PHE B:432 THR B:435 SER A:440 THR A:435 PHE A:432 SER B:440 ASN B:436 | SER A:440 THR A:435 PHE A:432 THR B:542 ASN B:436 LEU A:405 VAL B:546 |
Hydrogen bonds | ASN B:436 | ASN B:436 | MET B:549 | ASN A:436 | MET A:549 | MET B:549 | ASN A:436 |
Carbon–hydrgen interactions | THR A:435 | ASN A:436 | ASN A:436 | ASN B:436 | ASN A:436 ASN B:436 | ASN A:436 | |
π-type interactions | PHE A:439 PHE B:439 | PHE A:439 PHE B:439 | MET A:549 PHE B:439 PHE A:439 | PHE A:439 PHE B:439 | PHE A:439 PHE B:439 | PHE B:439 PHE B:439 | PHE B:439 PHE A:439 |
π–alkyl/alkyl | VAL A:546 VAL B:546 MET A:549 PHE B:432 | VAL A:546 VAL B:546 MET A:549 PHE A:439 | VAL A:546 VAL B:546 PHE A:439 | VAL A:546 VAL B:546 MET B:549 PHE B:439 | VAL A:546 VAL B:546 MET B:549 PHE B:439 | VAL A:546 VAL B:546 MET A:549 PHE A:439 | VAL A:546 MET B:549 PHE A:439 |
Sulfur interactions | MET B:549 | MET B:549 | MET B:549 | MET B:549 MET A:549 | MET B:549 | MET B:549 | MET A:549 |
M7 | M8 | M9 | M10 | M11 | M12 | |
---|---|---|---|---|---|---|
van der Waals interactions | PHE B:432 THR B:435 SER A:440 THR A:435 PHE A:432 SER B:440 ASN A:436 | PHE B:432 THR B:435 SER A:440 THR A:435 SER B:440 ASN A:436 ASN B:436 ILE B:543 | PHE B:432 THR A:435 PHE A:432 SER B:440 ASN A:436 ASN B:436 LEU A:405 THR A:435 | LEU B:405 THR B:435 THR A:435 SER B:440 ASN A:436 | PHE B:432 THR B:432 THR A:435 PHE A:432 ASN A:436 ASN B:436 | LEU B:405 PHE B:432 THR B:435 SER A:440 THR A:435 PHE A:432 SER B:440 ILE A:543 VAL B:401 |
Hydrogen bonds | MET B:549 ASN B:436 | |||||
Carbon–hydrogen interactions | ASN B:436 | THR B:542 | PHE A:439 | ASN A:436 | ||
π-type interactions | PHE A:439 PHE A:439 | PHE A:439 PHE A:439 PHE B:439 | PHE A:439 PHE A:439 PHE B:439 | PHE A:439 PHE B:439 | PHE A:439 PHE B:439 | PHE A:439 PHE B:439 |
π–alkyl/alkyl | VAL A:546 VAL B:546 MET B:549 PHE B:439 | VAL A:546 VAL B:546 | VAL B:546 MET A:549 PHE B:439 | VAL A:546 MET A:549 MET B:549 PHE A:432 PHE B:432 | VAL A:546 VAL B:546 MET A:549 MET B:549 PHE A:439 PHE B:439 | VAL A:546 VAL B:546 PHE A:439 |
Sulfur interactions | MET A:549 | MET B:549 MET A:549 | MET B:549 | MET A:549 | MET B:549 MET A:549 |
Compound | Binding Free Energy (MD) (kcal/mol) | ||
---|---|---|---|
TOPO-I/DNA | BRD4 | ABCG2 | |
M0 | −18.19 ± 2.53 | −22.21 ± 2.69 | −25.42 ± 2.93 |
M1 | −19.57 ± 2.52 | −21.60 ± 1.78 | −30.41 ± 1.93 |
M2 | −15.01 ± 2.67 | −15.48 ± 1.87 | −35.00 ± 3.06 |
M3 | −24.98 ± 2.65 | −25.92 ± 3.71 | −37.62 ± 3.73 |
M4 | −21.13 ± 3.23 | −17.60 ± 1.86 | −38.99 ± 2.22 |
M5 | −22.74 ± 1.29 | −21.02 ± 2.45 | −36.24 ± 1.80 |
M6 | −18.97 ± 1.38 | −24.67 ± 2.53 | −36.05 ± 2.05 |
M7 | −24.09 ± 1.05 | −23.84 ± 2.63 | −37.36 ± 2.11 |
M8 | −23.87 ± 1.39 | −19.93 ± 2.15 | −37.76 ± 1.51 |
M9 | −23.63 ± 3.25 | −21.28 ± 2.77 | −43.97 ± 1.83 |
M10 | −19.50 ± 2.24 | −22.01 ± 1.94 | −34.06 ± 3.06 |
M11 | −28.73 ± 1.26 | −23.76 ± 2.23 | −28.10 ± 2.40 |
M12 | −22.67 ± 2.96 | −25.06 ± 2.61 | −38.89 ± 2.09 |
Property | MW [Da] | HBA | HBD | Nrot | TPSA [Å2] | logP | logS | SAscore |
---|---|---|---|---|---|---|---|---|
M0 | 392.14 | 7 | 2 | 2 | 101.65 | 1.045 | −3.581 | - |
M1 | 332.17 | 6 | 2 | 5 | 80.68 | 1.027 | −2.407 | 4.27 |
M2 | 372.17 | 7 | 1 | 7 | 86.75 | 1.530 | −2.786 | 3.83 |
M3 | 371.18 | 7 | 2 | 7 | 89.55 | 1.551 | −2.775 | 3.86 |
M4 | 344.17 | 6 | 1 | 6 | 69.68 | 1.935 | −3.077 | 3.70 |
M5 | 357.17 | 7 | 3 | 6 | 103.54 | 0.963 | −2.608 | 3.70 |
M6 | 358.15 | 7 | 2 | 6 | 97.75 | 1.491 | −3.109 | 3.69 |
M7 | 356.17 | 6 | 1 | 6 | 77.52 | 1.813 | −3.069 | 3.73 |
M8 | 372.17 | 7 | 1 | 7 | 86.75 | 2.073 | −3.247 | 3.83 |
M9 | 386.18 | 7 | 1 | 8 | 86.75 | 2.631 | −3.528 | 3.97 |
M10 | 328.18 | 5 | 1 | 5 | 60.45 | 2.587 | −3.418 | 3.67 |
M11 | 314.16 | 5 | 1 | 5 | 60.45 | 1.857 | −2.910 | 3.56 |
M12 | 385.20 | 7 | 2 | 8 | 89.55 | 1.394 | −2.496 | 3.89 |
Property | Caco-2 | MDCK | Pgp Inhibitor | Pgp Substrate | Plasma Protein-Binding Parameter |
---|---|---|---|---|---|
M0 | −5.154 | −4.794 | --- | +++ | 98.89% |
M1 | −5.030 | −4.858 | --- | - | 61.40% |
M2 | −4.958 | −4.652 | - | + | 83.10% |
M3 | −4.987 | −4.633 | --- | -- | 80.30% |
M4 | −4.925 | −4.671 | + | - | 89.80% |
M5 | −5.117 | −4.623 | --- | - | 74.90% |
M6 | −5.117 | −4.984 | --- | --- | 91.20% |
M7 | −4.987 | −4.764 | + | --- | 91.00% |
M8 | −5.008 | −4.716 | ++ | -- | 97.30% |
M9 | −4.990 | −4.698 | + | --- | 96.50% |
M10 | −4.934 | −4.612 | ++ | --- | 95.20% |
M11 | −4.902 | −4.611 | - | + | 95.60% |
M12 | −4.923 | −4.615 | --- | +++ | 82.50% |
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Czyżnikowska, Ż.; Mysłek, M.; Marciniak, A.; Płaczek, R.; Kotynia, A.; Krzyżak, E. In Silico Approach to Design of New Multi-Targeted Inhibitors Based on Quinoline Ring with Potential Anticancer Properties. Int. J. Mol. Sci. 2025, 26, 4620. https://doi.org/10.3390/ijms26104620
Czyżnikowska Ż, Mysłek M, Marciniak A, Płaczek R, Kotynia A, Krzyżak E. In Silico Approach to Design of New Multi-Targeted Inhibitors Based on Quinoline Ring with Potential Anticancer Properties. International Journal of Molecular Sciences. 2025; 26(10):4620. https://doi.org/10.3390/ijms26104620
Chicago/Turabian StyleCzyżnikowska, Żaneta, Martyna Mysłek, Aleksandra Marciniak, Remigiusz Płaczek, Aleksandra Kotynia, and Edward Krzyżak. 2025. "In Silico Approach to Design of New Multi-Targeted Inhibitors Based on Quinoline Ring with Potential Anticancer Properties" International Journal of Molecular Sciences 26, no. 10: 4620. https://doi.org/10.3390/ijms26104620
APA StyleCzyżnikowska, Ż., Mysłek, M., Marciniak, A., Płaczek, R., Kotynia, A., & Krzyżak, E. (2025). In Silico Approach to Design of New Multi-Targeted Inhibitors Based on Quinoline Ring with Potential Anticancer Properties. International Journal of Molecular Sciences, 26(10), 4620. https://doi.org/10.3390/ijms26104620