In silico designing of some Benzimidazole derivatives for Anti-fungal activity
Amrita Muralikrishnan, Radhika R Nair, Jifitha Banu, Dr Leena K Pappachen
Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy,
Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, Kerala, India.
*Corresponding Author E-mail: leenakpappachen@aims.amrita.edu
ABSTRACT:
Fungus is a kind of living organism and yeast mould and mushrooms are types of fungi. The fungal infections are caused by the fungus. A fungus that invades the tissue can cause a disease that confined to the skin, spread into tissue, bone and organs or affect the whole body. Benzimidazole is a class of heterocyclic aromatic organic compound which posses pharmacological activities including antifungal, antitumor, antiparasitic, analgesic etc. Insilico methods can be used to identify target molecules using bioinformatics tool. The aim of our study was to conduct the insilico drug designing of some benzimidazole derivatives having antifungal activities. In our study the insilico drug design was performed using Biovia discovery studio.
KEYWORDS: Fungal diseases, Ketoconazole, Biovia Discovery studio, Benzimidazole, Molecular docking studies.
INTRODUCTION:
One may group fungal infections into two classes. The first category of fungal infection is mycoses of external surfaces such as the skin, skin structures and mucosa. The second main class of invasive fungal infections includes sterile body locations such as the bloodstream, CNS or organs like the lungs, liver and kidneys. Polyenes is the earliest group of antifungal medicines, the only example used for treating systemic fungal infections in this group being Amphotericin B.
Their severe toxicity has been one of the major drawbacks of polyenes, even though the production of Amphotericin B lipid preparations has greatly reduced this issue, these preparations are very costly and not accessible in some areas. Azole derivatives are the most commonly used class of antifungal drugs. The newest addition to the antifungal pharmacopeia is echinocandins with the first example, Capsofungin, launched a decade ago in clinical usage.3,4
Ketoconazole is an imidazole antifungal agent used in the prevention and treatment of a variety of fungal infections.14-α-sterol demethylase is a cytochrome P-450 enzyme essential for the transformation of lanosterol into ergosterol. Ketoconazole interacts with the enzyme and leads to ergosterol synthesis inhibition and increased fungal cellular permeability due to decreased levels of ergosterol present in the fungal cell membrane. This metabolic inhibition also leads to the build up of 14α-methyl-3,6-diol, a toxic metabolite.
MATERIALS AND METHODS:
Target identification:
Ketoconazole was selected as the standard drug for the study. The physical properties, chemical properties and mechanism of action of the drug was identified using the drug bank.
Protein selection and characterization:
The proteins were accessed from the protein data bank. The primary and secondary characterisation of the PDB ID’s obtained from the protein data bank were tested by using online tools such as PROTPARAM and SOPMA. The proteins must satisfy screening parameters including theoretical pH, half-life, instability index, aliphatic index, GRAVY, alpha helix, beta turn and random coil.5
Fig 1. Proteins selected for docking studies
Ligand modelling:
Ligand molecules were created with the help of ChemDraw.
|
SL NO |
STRUCTURE |
SL NO |
STRUCTURE |
|
B 1 |
|
B 5 |
|
|
B 2 |
|
B 6 |
|
|
B 3 |
|
B 7 |
|
|
B 4 |
|
B 8 |
|
Ligand characterisation:
Using Biovia Discovery Studio molecular pharmacophoric properties of ligand molecules including Alogp, molecular weight, HBD, HBA were calculated and compared with that of Ketoconazole.(6) Studies for the efficiency of absorption, distribution, metabolism and excretion in the body were conducted on the chosen ligands using prediction software Biovia ADMET.
Docking:
The docking studies of benzimidazole derivatives and standard drug Ketoconazole with known anti-fungal target proteins were carried out using Biovia discovery studio. The Cdocker energy and Cdocker interaction energy of benzimidazole derivatives were compared with that of Ketoconazole. (7,8)
RESULTS:
Protein characterisation
Table 1 PROTPARAM
|
Protein |
T1/2 |
Instability index |
Aliphatic index |
Gravy |
pH |
|
5 ESI |
30 |
38.89 |
85.90 |
-0.262 |
8.76 |
|
5 ESG |
30 |
38.50 |
85.90 |
-0.267 |
8.66 |
|
5 ESM |
30 |
38.50 |
85.90 |
-0.267 |
8.66 |
Table 2 SOPMA
|
Protein |
Α helix |
Β turn |
Random coil |
|
5 ESI |
250 is 4.38% |
19 is 9.53% |
21 is 40.07% |
|
5 ESG |
254 is 47.12% |
18 is 3.34% |
209 is 38.78% |
|
5 ESM |
253 is 46.94% |
21 is 3.90% |
205 is 38.03% |
Ligand characterisation:
Table 3 Lipinski rule of five
|
Structure |
A log p |
Number of HBA |
Number of HBD |
Molecular weight |
|
PROTEIN – 5ESG |
||||
|
B 1 |
2.625 |
1 |
1 |
180.634 |
|
B 2 |
2.887 |
1 |
1 |
245.504 |
|
B 3 |
3.11 |
1 |
1 |
194.661 |
|
B 4 |
2.625 |
1 |
1 |
180.634 |
|
B 5 |
2.887 |
1 |
1 |
245.504 |
|
B 6 |
2.344 |
1 |
1 |
184.598 |
|
B 7 |
2.112 |
2 |
1 |
211.623 |
|
B 8 |
2.128 |
3 |
1 |
231.611 |
|
KETOCONAZOLE |
3.610 |
5 |
0 |
531.431 |
|
PROTEIN – 5 ESM |
||||
|
B 1 |
2.625 |
1 |
1 |
180.634 |
|
B 2 |
3.378 |
1 |
1 |
326.416 |
|
B 3 |
3.602 |
1 |
1 |
275.573 |
|
B 4 |
3.116 |
1 |
1 |
261.546 |
|
B 5 |
3.378 |
1 |
1 |
326.416 |
|
B 6 |
2.835 |
1 |
1 |
265.51 |
|
B 7 |
2.508 |
1 |
1 |
272.529 |
|
B 8 |
2.524 |
1 |
1 |
292.517 |
|
KETOCONAZOLE |
3.610 |
5 |
0 |
531.431 |
|
PROTEIN – 5 ESI |
||||
|
B 1 |
2.625 |
1 |
1 |
180.634 |
|
B 2 |
3.378 |
1 |
1 |
326.416 |
|
B 3 |
3.662 |
1 |
1 |
275.573 |
|
B 4 |
3.116 |
1 |
1 |
261.546 |
|
B 5 |
3.378 |
1 |
1 |
326.416 |
|
B 6 |
2.835 |
1 |
1 |
265.51 |
|
B 7 |
2.508 |
2 |
1 |
272.529 |
|
B 8 |
2.524 |
3 |
1 |
292.517 |
|
KETOCONAZOLE |
3.610 |
5 |
0 |
531.431 |
Table 4 ADMET properties
|
Structure |
BBB |
Absoprtion |
Solubility |
Hepatotoxicity |
|
PROTEIN – 5 ESG |
||||
|
B 1 |
1 |
0 |
3 |
True |
|
B 2 |
1 |
0 |
3 |
True |
|
B 3 |
1 |
0 |
3 |
True |
|
B 4 |
1 |
0 |
3 |
True |
|
B 5 |
1 |
0 |
3 |
True |
|
B 6 |
1 |
0 |
3 |
True |
|
B 7 |
2 |
0 |
3 |
True |
|
B 8 |
3 |
0 |
3 |
True |
|
KETOCOAZOLE |
2 |
0 |
2 |
False |
|
PROTEIN – 5 ESM |
||||
|
B 1 |
1 |
0 |
3 |
True |
|
B 2 |
1 |
0 |
3 |
True |
|
B 3 |
1 |
0 |
2 |
True |
|
B 4 |
1 |
0 |
3 |
True |
|
B 5 |
1 |
0 |
3 |
True |
|
B 6 |
1 |
0 |
3 |
True |
|
B 7 |
2 |
0 |
3 |
True |
|
B 8 |
3 |
0 |
3 |
True |
|
KETOCONAZOLE |
2 |
0 |
2 |
False |
|
PROTEIN – 5 ESI |
||||
|
B 1 |
1 |
0 |
3 |
True |
|
B 2 |
1 |
0 |
3 |
True |
|
B 3 |
1 |
0 |
2 |
True |
|
B 4 |
1 |
0 |
3 |
True |
|
B 5 |
1 |
0 |
3 |
True |
|
B 6 |
2 |
0 |
3 |
True |
|
B 7 |
1 |
0 |
3 |
True |
|
B 8 |
2 |
0 |
3 |
True |
|
KETOCONAZOLE |
2 |
0 |
2 |
False |
Table 5 Docking
|
Structure |
Cdocker energy |
Cdocker interaction energy |
|
PROTEIN – 5 ESG |
||
|
B 1 |
19.5458 |
22.8988 |
|
B 2 |
18.4672 |
22.3552 |
|
B 3 |
18.9818 |
23.3467 |
|
B 4 |
17.3000 |
21.6862 |
|
B 5 |
17.6675 |
22.6273 |
|
B 6 |
11.4323 |
16.2301 |
|
B 7 |
17.5794 |
21.4091 |
|
B 8 |
14.9868 |
22.8106 |
|
KETOCOAZOLE |
30.1681 |
54.7465 |
|
PROTEIN – 5 ESM |
||
|
B 1 |
17.1007 |
20.4637 |
|
B 2 |
20.3209 |
23.992 |
|
B 3 |
20.7660 |
24.9263 |
|
B 4 |
17.5272 |
20.9952 |
|
B 5 |
18.1239 |
22.3651 |
|
B 6 |
11.5253 |
16.1806 |
|
B 7 |
18.6310 |
22.8956 |
|
B 8 |
8.8416 |
16.7218 |
|
KETOCOAZOLE |
31.2463 |
56.7017 |
|
PROTEINN – 5 ESI |
||
|
B 1 |
14.0416 |
17.5002 |
|
B 2 |
20.0818 |
23.9603 |
|
B 3 |
21.4308 |
25.5113 |
|
B 4 |
17.4488 |
20.7679 |
|
B 5 |
19.5579 |
23.8939 |
|
B 6 |
16.0872 |
20.8733 |
|
B 7 |
17.3514 |
21.8616 |
|
B 8 |
15.5148 |
22.9859 |
|
KETOCONAZOLE |
32.7041 |
57.9578 |
DISCUSSION:
All the generated benzimidazole derivatives satisfied the Lipinski’s rule of five. Comparison of benzimidazole derivatives docking scores with the standard drug Ketoconazole revealed that the derivatives exhibited a greater binding strength to the chosen proteins. Therefore, they offer exciting prospects for their antifungal activity to be investigated. The suggested benzimidazole derivatives are useful for further in vitro and in vivo studies against fungal infections.
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Received on 09.05.2020 Modified on 12.07.2020
Accepted on 16.08.2020 © RJPT All right reserved
Research J. Pharm. and Tech. 2021; 14(9):4983-4986.
DOI: 10.52711/0974-360X.2021.00867
