INTRODUCTION:

QSAR-

QSAR Quantitative structure-activity relationships (QSAR) have been applied for years in the development of relationships between physicochemical properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities^1,2. A quantitative structure-activity relationship (QSAR) is a mathematical relationship which correlates measurable or calculable molecular properties to some specific biological activity in terms of an equation. QSAR attempts to identify and quantify the physicochemical properties of a drug and to see whether any of these properties have an effect on the drugs biological activity^3–5.

In 3D QSAR, 3D properties of a molecule are considered as whole rather than considering individual substituent. This method involves the analysis of the quantitative relationship between the biological activity of a set of compounds and their three-dimensional properties using statistical correlation methods. It revolves around the important features of a molecule, its overall size and shape, and its electronic properties.

Antibiotics are the agents which inhibit growth or directly kill the bacteria or virus. There are different types of antibiotics, which work in their different way. However, the two main they work include: A bactericidal antibiotic, such as penicillin, kills the bacteria. These drugs usually interfere with either the formation of the bacterial cell wall or its cell contents. Bacteriostatic stops bacteria from multiplying. It may take a few hours or days after taking the first dose before people feel better or their symptoms improve. As bacteria become susceptible to old antibiotics and formed resistance, there are wide range of antibiotics developed in markets but to prevent further resistance by bacteria new antibiotics are restricted to formulate. So older antibiotics are modified and used for their desired purpose^6–8.

Classification of antibiotics- β-lactam, macrolide, tetracycline, aminoglycoside, quinolones, sulphonamide. In this review paper There are 2 categories such as Quinolones and aminoglycoside. Mechanism of action of Quinolonesexerts its antimicrobial activity via the inhibition of two key bacterial enzymes: DNA gyrase and topoisomerase IVBoth targets are type II topoisomerases, but have unique functions within the bacterial cell. DNA gyrase is an enzyme found only in bacteria that introduces negative supercoils into DNA during replication - this helps to relieve torsional strain caused by the introduction of positive supercoils during replication, and these negative supercoils are essential for chromosome condensation and the promotion of transcription initiation. It is comprised of four subunits (two A subunits and two B subunits) of which the A subunits appear to be the target of fluoroquinolone antibiotics. Bacterial topoisomerase IV, in addition to contributing to the relaxation of positive supercoils, is essential at the terminal stages of DNA replication and functions to “unlink” newly replicated chromosomes to allow for the completion of cell division. Inhibition of these enzymes by levofloxacin likely occurs via complexation with the topoisomerase enzymes. The end result is a blockade of DNA replication, thus inhibiting cell division and resulting in cell death.

Mechanism of action of Aminoglycosides involve disruption of Protein Synthesis-Aminoglycosides bind to the bacterial 30S ribosomal subunit. Ribosomes are the protein factories of cells. They are composed of two subunits in bacteria, a 30S and a larger 50S. Although the eukaryotic cells of humans also have ribosomes, these cellular protein factories differ in size and structure from the ribosomes of prokaryotes. That is why aminoglycosides do not interfere with protein synthesis in human cells. Bacterial Cell Wall Damage It may not be the inhibition of protein synthesis that produces the bactericidal (bacteria killing) effect. Aminoglycosides also appear to displace cations in the bacterial cell biofilm that are responsible for linking the lipopolysaccharide (LPS) molecules characteristic of Gram-negative bacterial cell walls. This creates holes in the cell wall that may kill the bacteria before the aminoglycoside even reaches the ribosome. Because our cells do not have cell walls (some of the chemical structural components of the bacterial cell wall are found only bacteria) human cells are not susceptible to these destructive actions^2,9,10.

QSAR Study of Ciprofloxacin:

Initially the molecular docking of ligand checked against PDB: 4dmg for antibiotic activity^11–13. The docking result of phenothiazine is -8.6kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residueIsolucine A141, alkyl bond formed with Selenomethionine to the ring containing 2 nitrogen, Pi alkyl bond formed in benzene ring and Isolucine A141.

Fig.1 -The interaction between Ciprofloxacin and PDB: 4dmg

1. Attachment of Functional group to nitrogen from main ring is removed which decreases activity. The molecular docking of ligand checked against PDB: 4dmg for antibiotic activity. The docking result of compound after modification is -7.1kcal/mol. Compound forms 6 different type of bond such as 1 convectional bond with lysine B740 another formed with convectional bond with ProB532

Fig.2 -The interaction between Compound 1 and PDB: 4dmg

2. At C2 Position CH₃ group is added, activity get decreased. The molecular docking of ligand checked against PDB: 4dmg for antibiotic activity. The docking result of compound after modification is -6.5kcal/mol. Compound forms 2 carbon hydrogen bond with ASP A297 and GLY A300, 2 Alkyl bonds are formed with PRO A95, 2 pi-alkyl bond formed with ILE A112 and MSE A301.

Fig.3- The interaction between Compound 2 and PDB: 4dmg

3. The molecular docking of ligand checked against PDB: 4dmg for antibiotic activity. The docking result of compound after modification is -6.9kcal/mol.3 convectional hydrogen bond formed by compound with GLY A110, ILE A112 and PRO A218, 2 alkyl bond formed by compound PRO A95 and ILE A112, 2 pi-alkyl bond formed by compound PRO A95 and ILE A112

Fig4- The interaction between Compound 3 and PDB: 4dmg

4. (=o) removed from C4 position, it will decrease its activity. The molecular docking of ligand checked against PDB: 4dmg for antibiotic activity. The docking result of compound after modification is -7.0kcal/mol.5 pi-alkyl bonds are formed by TRP B 647 and HIS B 669(2 bonds each) another one is by HIS643, 3 Alkyl bonds formed by ALA B404, VAL B606 & PRO B602, one pi-pi T-Shaped HIS B669

Fig.5-The interaction between Compound 4 and PDB: 4dmg

5. (=o) removed from COOH group at C3, activity will be decreased. The molecular docking of ligand checked against PDB: 4dmg for antibiotic activity. The docking result of compound after modification is -7.0kcal/mol. 2 carbon hydrogen bond formed by ASP A297 and GLY A300, 1 alkyl bond is formed by MSE A301.

Fig. 6- The interaction between Compound 5 and PDB: 4dmg

6. Ethane group attached to Nitrogen from C1, activity will be decreased. The molecular docking of ligand checked against PDB: 4dmg for antibiotic activity. The docking result of compound after modification is -6.7kcal/mol.3 carbon hydrogen formed by TRP A 436, GLU A141 and ILE A367, 3 Alkyl bond formed by ARG A371 and 2 are by ILE A367,2 convectional hydrogen bond formed by TRP A 436 & GLU A141, 1 Pi-alkyl bond is formed by ARG A371

Fig 7.-The interaction between Compound 6 and PDB: 4dmg

7. Cyclopropane attached to at C7 position. Activity will be minimum. The molecular docking of ligand checked against PDB: 4dmg for antibiotic activity. The docking result of compound after modification is -6.4kcal/mol.4 Pi-alkyl bonds were formed by TYR A100, MSE A101, ALA A128 & ILE A130,2 convectional hydrogen bond formed by LYS A 129 and ILE A130, 2 alkyl bonds are formed by MSE A101, 1 Pi-sigma bond is formed.

Fig.8The interaction between Compound 7 and PDB: 4dmg

QSAR Study of Streptomycin:

Initial Compound with maximum activity. Initially the molecular docking of ligand checked against PDB:5luh for antibiotic activity. The docking result of streptomycin is -8.6kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue TYR B34, GLN B87, GLN B108 ASP B128, Carbon hydrogen bond formed by ASP B130.

Fig.9 -The interaction between Streptomycin and PDB-5luh

1. Reduction of aldehyde to alcohol results in a compound dihydrostreptomycin activity is similar to streptomycin but producing severe deafness, activity get decreased. The molecular docking of ligand checked against PDB: 5luh for antibiotic activity. The docking result of compound after modification is -8.8kcal/mol, 9 convectional hydrogen bond formed by ASP B130, HIS B165, GLN B87, GLN B108, GLU B123, Attractive charge formed by TRP B 112, GLU B 123 and ASP B 128.

Fig.10 -The interaction between compound 1 and PDB-5luh

2. Oxidation of aldehyde group to a (oxime, semi carbazone, phenylhydrazone) Schiff base derivatives result in inactive analogues, activity increased. The molecular docking of ligand checked against PDB: 5luh for antibiotic activity. The docking result of compound after modification is -8.4kcal/mol, more than 10 convectional hydrogen bond formed by different amino acids, 2 pi alkyl bonds formed with TRP B173 and HIS B185.

Fig.11- The interaction between compound 2 and PDB-5luh

3. Oxidation of methyl group in a-streptose to a methylene hydroxy gives an active analogous but has no advantage over STM, activity get decreased. The molecular docking of ligand checked against PDB: 5luh for antibiotic activity. The docking result of compound after modification is -8.7kcal/mol, more than 6 convectional hydrogen bond formed by different amino acids, 2 attractive charge bonds formed with ASP B128 and ASP B130, 1 carbon hydrogen bond formed by GLN B87.

Fig.12- The interaction between compound 3 and PDB-5luh

4. Modification of amino methyl group in the glucosamine demethylation and replace by larger alkyl groups reduces activity. The molecular docking of ligand checked against PDB: 5luh for antibiotic activity. The docking result of compound after modification is -8.8kcal/mol, more than 14 convectional hydrogen bond formed by different amino acids, HIS A185 formed two different type of bond such as Pi-sigma and Pi-alkyl, other bonds also formed like attractive charge, etc.

13- The interaction between compound 4 and PDB-5luh

5. Guanidino groups streptidine ring are essential. Replacement of guanidino groups reduces the antibacterial activity. But here activity increased. The docking result of compound after modification is -8.2kcal/mol, more than 4 convectional hydrogen bond formed by ARG B 105, GIN B87, ASP B47, LYS B205, One Pi-alkyl bond formed by GLN B87, one carbon hydrogen bond formed by TRP B112.

Fig.14- The interaction between compound 5 and PDB-5luh

6. In N-Methyl-L-glucosamine the "N" atom should be secondary, activity get decreased. . The docking result of compound after modification is -9.0kcal/mol, more than 13 convectional hydrogen bond formed different amino acid. Pi-alkyl bond formed by GLN B87, one carbon hydrogen bond formed by TRP B112, two different unfavourable bonds formed by LYS B205.

Fig.15-The interaction between compound 6 and PDB-5luh

7. (=o) from N-Methyl L-Glucosamine ring is removed, results in decreased activity. The docking result of compound after modification is -9.1kcal/mol, 8 convectional hydrogen bond formed by different amino acid, 5 unfavourable bonds formed by two bonds by SERB36, GLN B108, ARG B105.

Fig.16- The interaction between compound 7 and PDB-5luh

CONCLUSION:

In the modern era of drug design and drug discovery molecular docking become very much important tool. Molecular docking provides large variety of analytical data about protein and drug. In this research Molecular docking of Ciprofloxacin and Streptomycin from antibiotic category performed. After made changes in chemical structure of drug as per SAR suggests data conclude that, In Ciprofloxacin attachment of functional group to nitrogen from first ring is removed which decreases activity extremely, Removed Fluorine group from C6 position decreases activity in moderate range and Cyclopropane attached to at C7 position activity remain same.

In Streptomycin, In N-Methyl-L-glucosamine the "N" atom should be secondary, activity but after changing it activity decreasedextremely. In case of oxidation of methyl group in a-streptose to a methylene hydroxy gives an active analogous but has no advantage over STM, activity get decreased slightly and after oxidation of aldehyde group to a (oxime, semi carbazone, phenylhydrazone) Schiff base derivatives result in inactive analogues, activity get increased.

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Received on 29.04.2023 Modified on 27.10.2023

Asian J. Pharm. Tech. 2024; 14(3):289-295.

DOI: 10.52711/2231-5713.2024.00047