Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder mainly characterized by progressive deterioration of memory and impaired cognitive function. The most promising approach for symptomatic relief of AD is to inhibit acetylcholinesterase (AChE). On the basis of this approach in-house library of 9-aminoacridine derivatives were constructed and allowed to docked against human acetylcholinesterase (hAChE) (PDB ID: 4EY7), using MOE 2018.01 and PyRx 0.9.2 (AutoDock Vina). Top ranked and best fitted molecules were synthesized by targeting the 9-amino group of aminoacridine with substituted phenacyl halides. Anti-Alzheimer's potential was checked by in vitro AChE inhibition, antioxidant activity (DPPH scavenging ability) and fibril disaggregation. Subjected ligands suggested as promising multitargeted candidate with pronounced results in term of IC50 values (AChE inhibition 2.400-26.138μM), however, none of them showed potential towards fibril inhibition.
Acetylcholine esterase (AChE) is a key biological target responsible for the management of cholinergic transmission, and its inhibitors are used for the therapy of Alzheimer's disease. In the present study, a small library of molecules with 1,3-di-4-piperidylpropane nucleus were docked on AChE. The selected compounds were synthesized and evaluated for their enzyme inhibition. P25 and P17 expressed significantly higher AChE inhibition than standards with IC50 values of 0.591μM and 0.625μM, respectively. Binding mode of derivatives in the active site of AChE revealed dual binding of molecules in peripheral anionic site (PAS) and catalytic anionic site (CAS) of enzyme cavity.
The impact of computer-aided drug designing in the field of medicinal chemistry has created a boon in the drug discovery process. Molecular docking is an integral part of bioinformatics that deals with protein-ligand interactions, binding conformations, and affinity predictions. It has shown to be a rapid, easy, and affordable method in business and research settings alike. The advancement in the hardware and software has led to enhanced molecular dynamic simulations and thus authenticate the computational results. This has created a great impact in minimizing the cost and time involved in the drug discovery process. It has also helped in identifying the rationale for drug repurposing approaches. This chapter will give in-depth knowledge of the importance of molecular docking in drug designing and discovery, their impact on drug repurposing, and success stories of the in silico approach in drug discovery and repurposing.
Benzimidazole and its derivatives found variety of biological activities, for the searching of its potent anti-inflammatory analogues, we synthesized four novel 4-(2-keto-1-benzimidazollinyl) piperidine derivatives (Q1 to Q4) by refluxing piperidine with substituted imidazole and subjected to in-vitro anti-inflammatory (ROS, NO) and antibacterial activities, structures were elucidated using spectroscopic techniques. Results revealed that compound Q1 showed most effective anti-inflammatory activity with IC 50 7.6±1.3 μg/ml compared with standard Ibuprofen having IC50 11.2±1.9μg/mL. Compound Q3 showed good activity for Nitrite accumulation by stimulating macrophages test similar to standard NG Methyl L-arginine acetate with IC50 value 24.2±0.8μg/mL. The antibacterial activity of these compounds were evaluated against selected Gram+ve E. faecalis, C. diphtheriae, S. aureus and Gram -ve organism E. coli, Enterobacter aerogenes and P. aeruginosa. Synthesized compounds showed low to moderate level of antibacterial activity Q1 showed the highest antibacterial activity against Enterococcus faecalis and Escherichia coli with zone of inhibition 18mm and Q3 showed highest activity against Corynebacterium diptheriae (ZOI:18mm). Structure-activity relationship (SAR) study revealed that among all the synthesized compounds unsubstituted naphthalene (Q1) and phenyl (Q3) ring containing derivatives were most potent.
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