Introduction
Imidazo[2,1-b] 1, 4, 2, 3 Thiadiazole 1 is a bridgehead nitrogen atom heterocyclic. This compound was discovered in the early 1950s which is composed of four heteroatom and two condensed heterocycles with different -conjugations. This heterocycle is an isoster of biologically significant imidazo 1, 4, 2, 3 thiazole, in which the thiazole ring's 3-CH group is replaced by a 3-N atom. The majority of the synthesised compounds have been reported to have a wide range of biological activities as well as the ability to block certain enzymes. Antibacterial, antifungal, leishmanicidal, herbicidal, antitubercular, anticancer, anthelmintic, anticonvulsant, analgesic, antiinflammatory, antipyretic, local anaesthetic, cardiotonic, and diuretic are among the biological activities. Staphylococcus aureus is a common cause of skin infections, respiratory infections, sinusitis and food poisoning. It is also responsible for life threatening diseases. Each year up to 50,000 deaths each year in USA are linked with S. aureus infection. In this report reveals the information of some new molecules of benzimidazole derivative is reported active against S. aureus. Molecular docking is a kind of bioinformatic modelling which includes the interplay of two or more molecules to present the solid adduct. Depending upon binding residences of ligand and target, it predicts the 3-dimensional structure of any complex drug molecule. Molecular docking generates distinct possible adduct structures which can be ranked and grouped together by the use of scoring feature inside the software program.
Conducting DMPK (Drug Metabolism and Pharmacokinetics) research, also known as ADMET (Absorption, Distribution, Metabolism, Elimination, and Toxicity) investigations, is an important part of drug discovery and development. These studies aid in determining a medicaments feasibility by explaining terms like absorption, distribution, metabolism and elimination and toxicity.
Material and Methods
Designing of compounds
29 derivatives of imidazol[2,1-b] 1, 2, 3Thiadiazole has been designed by substitution of different groups at R1,R2 and R3 positions.
Drawing of 2D and 3D structure of compounds and energy minimization
Two dimensional structures of all the 29 compounds were drawn by using software chem Draw ultra 8.0. Prepared 2D structures were converted into 3D structure by using chem. 3D ultra 8.0. Then 3D structures were optimized by performing energy minimization via molecular mechanics amd re-optimized by using molecular orbital package (MOPAC) until the RMS value became 0.0001Kcal/mol.
Docking procedure
Three dimensional (3D) structure of PDBCode: 4LAE protein ligand was downloaded for from protein data bank. 3D structure of 4LAE protein ligand and designed compounds were imported in the work area space of molegro virtual docker (ver 6.0) and the required bonds, hybridization bond order hydrogen atom and charges were subjected. Surface created and the active site analyzed. Water molecule is removed because it is not consider during docking process. The binding active sites were analyzed through automated process. Grid resolution, probe size were adjusted. After that docking calculation started, Mol Dock score and rerank score of designed compounds were noted.5
ADMET Studies
Absorption, distribution, metabolism, elimination and toxicity studies were performed on top five compounds 5B, 5G, 5H, 5N and 5Q and the data generated by using computational ADMET software and result was recorded.6, 7, 8, 9, 10, 11, 12
Result and Discussion
29 compounds of imidazole derivatives were designed on the basis of literature review and docking was performed against Staphylococcus aureus and co crystallized with PDB code 4LAE protein ligand. The co crystallized ligand of PDB 4LAE protein ligand was also validated. The mole dock score, Rerank score and the amino acid interactions are reported in the Table 1. And the amino acid intractions of maximum compound were matched with interaction of 4LAE protein ligand PDB.13
Table 1
Molecular docking results of five most active compounds.
The prediction of ADMET properties is critical in the drug design process because these features are responsible for around 60% of all medication failures in clinical trials. Whereas in the past, ADME techniques were used at the conclusion of the drug development process, today ADME is used from the beginning of the process to eliminate compounds with poor ADME features from the drug development pipeline, resulting in significant research and development cost savings. The ADMET studies performed in this research article show the good ADME properties of drug and hence, these molecules can further proceed in relation to discover the new molecule of imidazole derivative against microbial activity. The result of ADMET studies of top five molecules of imidazole derivative are metioned in Table 2.
Table 2
ADMET results of five most active compounds.
Among all the 29 compounds of imidazole derivatives, five compounds (5B, 5G, 5H, 5N and 5Q) showed highest binding affinity on the basis of mole dock score. And good ADMET value on the basis of computation ADMET tool. Hence, this five molecules were estimated as most potent molecules as antibacterial agent.
Summary and Conclusion
In conclusion it is estimated through molecular docking that compounds which are having nitro group substitution at R3 position show good anti-bacterial properties then other aginst S. aureus. Out of twenty nine compound Good pharmacokinetic properties of 5b, 5g, 5h, 5n and 5q were investigated through ADME studies. The ADMET studies performed in this research article show the good ADME properties of drug and hence, these molecules can further proceed in relation to discover the new molecule of imidazole derivative against microbial activity.
