Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations
Abstract
1. Introduction
2. Details of Molecular Simulations
2.1. Proposal of Novel ZZ3 Derivatives as Potent Inhibitors of FtsZ
2.2. Constructions and Optimizations of the FtsZ + Derivative Complexes
2.3. FMO Calculations for the FtsZ + Derivative Complexes
3. Results and Discussion
3.1. Binding Properties between FtsZ and the ZZ3 Derivatives by Replacing A-Part
3.2. Binding Properties between FtsZ and the ZZ3 Derivatives by Replacing the B- or D-Part
4. Conclusions
- (1)
- The derivative, ZZ3_X, in which an OH group was introduced in the D-part of ZZ3, possessed the largest BE to FtsZ due to the strong H-bond between the OH group and Asp165 side chain.
- (2)
- Since Asp165 was included in the H6/H7 loop, which was beneficial for the aggregation of FtsZ, ZZ3_X was expected to change the conformation of the loop to inhibit the aggregations.
- (3)
- The replacement of the A- and B-parts of ZZ3 did not exert any positive effect on the enhancement of the interactions between ZZ3 and FtsZ.
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Ligand | MW | RB | HBA | HBD | LogP | PSA |
---|---|---|---|---|---|---|
Z3 | 431.0 | 8 | 3 | 1 | 4.65 | 3.33 |
ZZ3 | 402.9 | 6 | 3 | 1 | 4.24 | 3.12 |
ZZ3_II | 402.9 | 7 | 3 | 2 | 4.24 | 3.11 |
ZZ3_III | 417.0 | 7 | 3 | 1 | 4.45 | 3.22 |
ZZ3_IV | 388.9 | 6 | 3 | 2 | 4.04 | 3.01 |
ZZ3_V | 374.9 | 5 | 3 | 2 | 3.83 | 2.87 |
ZZ3_VI | 403.9 | 7 | 3 | 1 | 4.24 | 3.09 |
ZZ3_VII | 389.9 | 6 | 3 | 1 | 4.04 | 2.96 |
ZZ3_VIII | 375.9 | 5 | 3 | 2 | 3.83 | 2.82 |
ZZ3_IX | 417.0 | 7 | 3 | 1 | 4.45 | 3.21 |
ZZ3_X | 418.9 | 6 | 4 | 2 | 3.42 | 3.11 |
ZZ3_XI | 418.9 | 6 | 4 | 2 | 3.42 | 3.09 |
ZZ3_XII | 418.9 | 6 | 4 | 2 | 3.42 | 3.17 |
ZZ3_XIII | 417.0 | 6 | 3 | 1 | 4.45 | 3.25 |
ZZ3_XIV | 417.0 | 6 | 3 | 1 | 4.45 | 3.24 |
ZZ3_XV | 417.0 | 6 | 3 | 1 | 4.45 | 3.27 |
Ligand | BBB | Caco2 | HIA | PPB | Mouse | Rat | hERG |
---|---|---|---|---|---|---|---|
Z3 | 3.5 | 55.6 | 97.1 | 86.7 | positive | negative | medium |
ZZ3 | 1.5 | 54.3 | 97.1 | 84.4 | positive | negative | medium |
ZZ3_II | 4.2 | 48.2 | 95.9 | 91.9 | positive | negative | medium |
ZZ3_III | 2.4 | 55.0 | 97.1 | 85.1 | positive | negative | medium |
ZZ3_IV | 3.1 | 45.8 | 95.9 | 86.6 | positive | negative | medium |
ZZ3_V | 0.5 | 25.8 | 96.3 | 95.8 | positive | negative | medium |
ZZ3_VI | 1.0 | 53.5 | 97.1 | 91.8 | positive | negative | medium |
ZZ3_VII | 0.6 | 52.0 | 97.1 | 91.1 | positive | negative | medium |
ZZ3_VIII | 2.4 | 29.8 | 95.9 | 92.3 | positive | negative | medium |
ZZ3_IX | 1.7 | 54.9 | 97.1 | 83.3 | positive | negative | medium |
ZZ3_X | 2.8 | 37.6 | 96.1 | 84.4 | negative | negative | medium |
ZZ3_XI | 2.8 | 37.6 | 96.1 | 85.3 | positive | negative | medium |
ZZ3_XII | 2.8 | 37.6 | 96.1 | 85.0 | positive | negative | medium |
ZZ3_XIII | 2.8 | 54.4 | 97.1 | 84.5 | positive | negative | medium |
ZZ3_XIV | 3.1 | 54.4 | 97.1 | 84.2 | positive | negative | medium |
ZZ3_XV | 2.7 | 54.4 | 97.1 | 84.1 | positive | negative | medium |
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Yamamoto, S.; Saito, R.; Nakamura, S.; Sogawa, H.; Karpov, P.; Shulga, S.; Blume, Y.; Kurita, N. Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations. Antibiotics 2020, 9, 846. https://doi.org/10.3390/antibiotics9120846
Yamamoto S, Saito R, Nakamura S, Sogawa H, Karpov P, Shulga S, Blume Y, Kurita N. Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations. Antibiotics. 2020; 9(12):846. https://doi.org/10.3390/antibiotics9120846
Chicago/Turabian StyleYamamoto, Shohei, Ryosuke Saito, Shunya Nakamura, Haruki Sogawa, Pavel Karpov, Sergey Shulga, Yaroslav Blume, and Noriyuki Kurita. 2020. "Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations" Antibiotics 9, no. 12: 846. https://doi.org/10.3390/antibiotics9120846
APA StyleYamamoto, S., Saito, R., Nakamura, S., Sogawa, H., Karpov, P., Shulga, S., Blume, Y., & Kurita, N. (2020). Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations. Antibiotics, 9(12), 846. https://doi.org/10.3390/antibiotics9120846