1MPharm Student, Department of Pharmaceutical Chemistry, Prime College of Pharmacy, Palakkad, Kerala, 67855
2Associate Professor, Department of Pharmaceutical Analysis, Prime College of Pharmacy, Palakkad, Kerala,67855
3Head of department, Department of Pharmaceutical Chemistry, Prime College of Pharmacy, Palakkad, Kerala,678551
4Principal, Prime College of Pharmacy, Palakkad, Kerala,678551
Tuberculosis is prominent disease which is fatal so the newer medicines is required to face the drug resistance. Chalcone based derivatives being potential source for wide spectrum of ant proliferative, antibacterial, antimalarial pharmacological properties The designed compounds were screened using SWISS ADME and Osiris Property Explorer. The compound12,13,14,15,17 and 20 showed promising character for further research. The docking study using PyRx 0.8 also showed the commendable binding affinity more than 9.9 Kcal/moll comparing to standard Isoniazid 6.5Kcal/mol in InhA protein PDB ID :4TRO.
TB continues to be considered one of the deadliest transmissible diseases in the entire world. The necessity of developing new medicines is getting more pressing, especially since face of the spike in drug resistance. One potential strategy for the development of medications for TB is the use of chemical molecules named chalcones. Chalcones exist as trans (E) or cis (Z) isomers with two aromatic rings joined by an ?, ?-unsaturated ketone group (-C=O). Compounds developed from chalcones have shown immense potential in suppressing the activity of enoyl reductase, an enzyme for tuberculosis progress. These chalcone scaffold variants target the enzyme enoyl reductase, which is crucial for Mycobacterium tuberculosis's ability to generate mycolic acids. Chalcone-based compounds provide an innovative way for treating tuberculosis by disrupting this enzyme and enabling the bacterium to disrupt critical metabolic pathways. It can combat drug-resistant strains of the illness is studying the potential of chalcone derivatives as enoyl reductase inhibitors.
The Potential of Chalcone Derivatives
Specific structural features of chalcones, such as the conjugated double bond system (enone functionality) and the presence of aromatic rings, are thought to contribute to their inhibitory activity against ERs. The naturally occurring existing form crystalline ranging from pale yellow solids to colours depending on substituent group present, while soluble in organic solvents like ethanol, acetone, dichloromethane chalcone bind to the active site of ERs, preventing them from converting enoyl-ACP (acyl carrier protein) substrates to fatty acids. It inhibits the bacteria's ability to synthesize their cell walls and other essential components. It has a new mechanism of action that may help overcome the growing antibiotic problem. As it has resistance in bacteria and from natural origin suggest possible lower toxicity and better tolerability. Studies in vitro and in silico on their activity have shown that one of the most important factors affecting the tuberculosis activity of chalcones is the lipophilicity of these molecules, which allows them to easily penetrate the cell wall of mycobacteria. The presence of hydrophobic groups as substitutes in clone rings A and B is also important from the point of view of better affinity to the enzymes they inhibit.
MATERIALS AND METHODS
Software used: -
ACD Chemsketch, Chem 3D Pro, PyRx 0.8, Biovia Discovery Studio 2024, Osiris Property Explorer 2017, SWISS ADME
ADME screening: -
The properties were obtained using SWISS ADME online where the smiles of the structure were used as input data. The drug likeness properties were also collected using SWISS ADME
Toxicity screening:-
Osiris property explorer was used to evaluate the toxicity effect of the compounds also depicting their solubility and drug score.
Target Protein Preparation: -
Protein was downloaded from Protein data bank(PDB:4TRO). The resolution 1.4 Ao.It comes under the classification of Oxidoreductase. Its expression system is Escherichia coli BL21(DE3). The protein was cleaned using Biovia Discovery Studio 2024.
Ligand preparation: -
The pool of carbazole based chalcones designed using ACD Chemsketch.The energy of the ligand was minimized using Chem 3D Pro.The ligands are saved as pdb file.
Docking:
-Pyrex 0.8 version was used for docking as it uses auto dock vina. The protein molecule was loaded and the molecules was converted to macromolecule. The ligand was opened in OpenBabel.The ligand energy was minimized and converted to pdbqt format. The docking was performed using vina wizard. The docking score was analyzed.
Post docking analysis: -
The cleaned protein was opened in Biovia Discovery Studio 2024.The docked pose was dragged into the cleaned protein. The ligand interaction and 2D diagram was obtained
Carbazole based various chalcone derivatives designed using Chemsketch.
Fig. 1. The general structure of carbazole based chalcone
Table I: Carbazole-Chalcone derivatives
RESULTS AND DISCUSSION
Lipinski rule of 5:-It predicts the oral bioavailability. Compound which has molecular weight (<500>
Table I: Drug Likeness of the derivatives
Compound 4,7,12,13,20 has Log P greater than 5. As none of the compounds has more than 1 violation all can be considered for further studies
ADMET screening: -
The failure of majority of drugs is due to insufficient absorption and in some case toxic effect being shown. Thus software is used for screening various parameters. (Table 2). Compound 12,13,14,15,17 does not cross the blood brain barrier. Except compound 18 all inhibit CYP1A2, CYP2C19, CYP2C9.The toxicity assessment show that all derivatives have lesser toxic effects and evaluable solubility (Table 3).
Table 2: ADME of the derivatives
Table 3: Toxicity assessment of the derivatives
Docking studies: -
The docking scores of the designed ligands are greater than the standard Isoniazid thus higher probability of binding to the protein. The docking score along with the amino acid which it forms H-bond, Hydrophobic bond are mentioned. (Table 4). The greater docking score possessing ligands 2D and 3D diagram are depicted 6,13,14,20 (Table 5)
Table 4: Molecular interaction of ccarbazole based chalcones with their docking score
Table 5:3D and 2D diagram of the selected derivatives
CONCLUSION:
TB treatment is a major challenge for global health. The synthesised chalcone compound being active against wide range spectrum of activity which also include antibacterial activity is being shown. The designed ligand subjected to drug likeness property which showed that all passes the Lipinski rule of 5.But as the ADMET screening showed that majority of the compounds can cross the blood brain barrier except compound 12,13,14,15,17,20.As the docking scores of all the compounds are greater than the standard drug it has greater rate for binding but also considering the ADMET studies the compound as 12,13,14,15,17,20 has been screen using various Insilco approach to go further for the synthesis, evaluation of Anti-Tb may lead to major breakthroughs in the treatment of tuberculosis..
REFERENCE :
M.G. Manu , S. Greeshma , A. Sumathy , N. L. Gowrishankar, Exploring the Anti-Tubercular Potential of Carbazole Chalcones: -An In Silico Approach, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 10, 224-235. https://doi.org/10.5281/zenodo.13894077
10.5281/zenodo.13894077
