In Silico Activity Prediction and Docking Studies of the Binding Mechanisms of Levofloxacin Structure Derivatives to Active Receptor Sites of Bacterial Type IIA Topoisomerases
Abstract
:1. Introduction
2. Materials and Methods
2.1. Fluoroquinolone Samples
2.2. QSAR
2.3. PASS
2.4. Software of Molecular Docking
2.5. Equipment for Tribochemical Processing
2.6. Fourier Transform IR Spectroscopy
2.7. Optical Microscopy (OM)
2.8. Statistical Data Processing
3. Results and Discussion
3.1. Structure-Activity Relationship Study
Experimenting In Silico (Chemicpen, PASS Online, ChemDescript)
3.2. Experimentation Using Tribochemical Processes
3.3. Binding Modes Prediction and Molecular Modeling
Visualization between RMS, Compounds of PMS, and DNA Gyrase II
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AntA | antimicrobial agents |
ANOVA | one-way analysis of variance |
MCh | mechanochemistry |
MAct | mechanoactivation |
TrbCh | tribochemical |
QNs | quinolones |
FlrQs | fluoroquinolones |
SMComplex | supramolecular complex |
FDA | Food and Drug Administration |
EMA | The European Medicines Agency |
ADR | adverse drug reactions |
TrbCh | tribochemical |
Lvf·Hh | levofloxacin hemihydrate |
QSAR | quantitative structure-activity relationship |
QRDR | Quinolone resistance determining region |
MIC | minimal inhibitory concentrations |
MRSA | Methicillin-Resistant Staphylococcus aureus |
MDR | Penicillin-resistant and multi-drug-resistant Streptococcus pneumonia |
RMS | real molecular structures |
PMS | predicted molecular structures |
PLD | predicted levofloxacin derivatives |
dLvf | 11-decarboxylated levofloxacin |
TI | topological index |
FT-IR | Fourier transform IR spectroscopy |
PASS | Prediction of Activity Spectra for Substances |
MNA | Multilevel neighborhoods of atoms |
LALLS | low-angle laser light scattering |
OM | optical microscopy |
DSA | dynamic strain aging |
2D-LS | two-dimensional dynamic backscattering |
ChRS | chemometric reference sample |
ETEC | enterotoxigenic Escherichia coli |
RMSD | Root Mean Square Deviation |
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Molecular Weight, g·mol−1 | Log Po/w | pKa (Strongest Acidic) | Water Solubility, mg·mL−1 | Toxicity in Mice LD50, mg·kg−1 | Microbiologic Activity/ Indications |
---|---|---|---|---|---|
NALIDIXIC ACID (FlrQ-1G) | |||||
232.2 | 1.6 | 8.60 | 0.1 | 4000 | Enterobacteriaceae/Uncomplicated urinary tract infections, not for use in systemic infections * |
CIPROFLOXACIN (FlrQ-2G) | |||||
331.3 | 0.3 | 6.10 | <1.00 | 2000 | Enterobacteriaceae, atypical pathogens; Pseudomonas aeruginosa, Pneumoccoci/ * and also complicated urinary tract and catheter-related infections, gastroenteritis |
LEVOFLOXACIN (FlrQ-3G) | |||||
361.4 | 0.7 | 5.50 | 1.44 | 1800 | Enterobacteriaceae, atypical pathogens, streptococci. Pneumoccoci MIC90: 0.25–0.5 mg·L−1/* and also community-acquired pneumonia in hospitalized patients or if atypical pathogens are strongly suspected |
MOXIFLOXACIN (FlrQ-4G) | |||||
401.4 | 2.9 | 5.49 | 1.15 | 100 | Enterobacteriaceae, P. aeruginosa, atypical pathogens, MSSA, streptococci, anaerobes, Pneumoccoci. Consider for treatment of intra-abdominal infections |
LEVONADIFLOXACIN (FlrQ-5G) | |||||
360.4 | 0.87 ** | 5.94 ** | 0.63 ** | 535 ** | Anti-MDR, MRSA, MDR S. pneumoniae, pathogenies ESKAPE, P. aeruginosa и S. aureus strains/hospital-acquired and nosocomial pneumonia, diabetic foot ulcer infections and skin and soft tissue infections, acute otitis eterna (swimmer’s ear) |
Topological Index | Definition | Equation |
---|---|---|
Wiener (W) | the shortest distances sum between all pairs of vertices in G graph | where dij is the shortest distance between vertices i and j |
Balaban (J) | the average distance-sum connectivity index | where n and m are the cardinalities of the vertex and the edge set of G, respectively, and w(u) (resp. w(v)) denotes the sum of distances from u (resp. v) to all the other vertices of G |
Detour (Ip) | the sum of the upper triangle of the detour | where the i,j-th entry ∆ij denotes the longest path between vertices i and j of the underlying graph (i, j = 1, 2, ... N) where N denotes the number of vertices |
Electropy (Ie) | the sum of the squares of the atomic nuclear charges divided by the square of the number of atoms in the molecule minus one | pa and pi represent the probabilities for the occurrence of an a priori event and i—posteriori event. The larger the Ie index value, the more electropositive the molecule is. |
№ | Lvf Structure Derivatives | Prediction Spectra of Biological Activity (Pa) | ||||||
---|---|---|---|---|---|---|---|---|
Ing TopII 1* | Ing DNAS 2* | SDAc 3* | QnAnMc 4* | AntBc 5* | AntTt 6* | Ing CYP1 A2 7* | ||
1 | basic | 0.851 | 0.818 | 0.797 | 0.653 | 0.636 | 0.559 | 0 |
2 | 6-decarboxylated | 0.699 | 0.620 | 0.811 | 0.351 | 0.818 | 0.589 | 0.716 |
3 | 9-defluorinated | 0.699 | 0.620 | 0.811 | 0.351 | 0.818 | 0.589 | 0.716 |
4 | 10-depyperazine | 0.756 | 0.634 | 0.753 | 0.495 | 0.575 | 0.347 | 0.467 |
5 | 4-benzoxazine-BCS | 0.472 | 0.487 | 0.699 | 0.095 | 0.426 | 0.455 | 0.518 |
6 | 5-dehydro-4-benzoxazine-BCS | 0.302 | 0.405 | 0.638 | 0.035 | 0.271 | 0.453 | 0.424 |
Ligand | Steric Interaction | Non-Steric Interaction | Affinity Values, kcal/mol | |||
---|---|---|---|---|---|---|
Gauss 1 | Gauss 2 | Repulsion | Hydrophobic Attraction | Non-Directional Hydrogen Bond | ||
basic Lvf | 7.50 | 91.97 | 0.16 | 0.29 | 0.08 | −9.7 |
9-defluorinated | 7.67 | 91.74 | 0.17 | 0.31 | 0.11 | −9.4 |
6-decarboxylated | 7.35 | 92.17 | 0.12 | 0.33 | 0.03 | −8.9 |
10-depyperazine | 8.66 | 90.84 | 0.19 | 0.19 | 0.12 | −8.6 |
Poses in Cluster | Best Pose | Binding Site Coordinates | Kb·105, M−1 |
---|---|---|---|
basic levofloxacin | 1.31 | ||
24 | 592 | (−22.18, 50.92, −37.92) | |
33 | 1201 | (−39.00, 54.45, −38.88) | |
69 | 232 | (−18.02, 26.50, −36.81) | |
9-defluorinated | 1.30 | ||
36 | 982 | (−22.25; 51.62, −38.84) | |
39 | 591 | (−39.10, 54.89, −38.22) | |
68 | 173 | (−18.43, 27.23, −36.66) | |
6-decarboxylated | 1.29 | ||
41 | 1228 | (−39,16, 54.97, −38.91) | |
41 | 1001 | (−22.00, 51.04, −38.77) | |
66 | 258 | (−17.54, 26.57, −36.31) | |
10-depyperazine | 1.28 | ||
54 | 1223 | (−38.84, 54.74, −37.11) | |
45 | 592 | (−22.03, 51.80, −37.31) | |
37 | 985 | (−18.27, 55.28, −25.49) |
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Uspenskaya, E.V.; Sukhanova, V.A.; Kuzmina, E.S.; Pleteneva, T.V.; Levitskaya, O.V.; Garaev, T.M.; Syroeshkin, A.V. In Silico Activity Prediction and Docking Studies of the Binding Mechanisms of Levofloxacin Structure Derivatives to Active Receptor Sites of Bacterial Type IIA Topoisomerases. Sci. Pharm. 2024, 92, 1. https://doi.org/10.3390/scipharm92010001
Uspenskaya EV, Sukhanova VA, Kuzmina ES, Pleteneva TV, Levitskaya OV, Garaev TM, Syroeshkin AV. In Silico Activity Prediction and Docking Studies of the Binding Mechanisms of Levofloxacin Structure Derivatives to Active Receptor Sites of Bacterial Type IIA Topoisomerases. Scientia Pharmaceutica. 2024; 92(1):1. https://doi.org/10.3390/scipharm92010001
Chicago/Turabian StyleUspenskaya, Elena V., Vasilisa A. Sukhanova, Ekaterina S. Kuzmina, Tatyana V. Pleteneva, Olga V. Levitskaya, Timur M. Garaev, and Anton V. Syroeshkin. 2024. "In Silico Activity Prediction and Docking Studies of the Binding Mechanisms of Levofloxacin Structure Derivatives to Active Receptor Sites of Bacterial Type IIA Topoisomerases" Scientia Pharmaceutica 92, no. 1: 1. https://doi.org/10.3390/scipharm92010001