👤 RajaSekhar Reddy Alavala

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme involved in tau hyperphosphorylation, a key pathological mechanism leading to tau aggregation and thus, Alzheimer's disease. It also has a significant role in neuroinflammation, induction of BACE1, and amyloid-β aggregation. Such crucial pathological events are involved intricately with the Alzheimer's disease pathophysiology which makes this enzyme an attractive drug target. Designing a competitive ATP-site inhibitor of GSK-3β is the approach adopted here in an attempt to target tau pathology. Tetrazole is selected as a scaffold taking into account the previously reported inhibitors bearing nitrogen heterocycles which are at the heart of drug design strategies. A library of disubstituted tetrazole analogs was designed and molecular docking was performed. The top 30 molecules were then passed through several ADMET filters with a special preference given to BBB permeability. The hit molecules obtained after this were analyzed for their amino acid interactions. The docked complexes were used to perform MD simulations for 100 ns and later MM-GBSA studies were performed with staurosporine and co-crystallized ligand as reference molecules. Furthermore, various chemical reactivity parameters and the HOMO-LUMO energy gap were analyzed with DFT studies using B3LYP functional. The best molecule obtained was TD30, revealing a docking score of -167.036, an average RMSD of 2.15 Å for 100 ns simulation time, average ΔG Show less

Alzheimer's disease is a neurodegenerative disorder accounting for 60-80% of dementia cases and is accompanied by a high mortality rate in patients above 70 years of age. The formation of senile plaques composed of amyloid-β protein is a hallmark of Alzheimer's disease. Beta-site APP cleaving enzyme 1 (BACE1) is a proteolytic enzyme involved in the degradation of amyloid precursor protein, which further degrades to form toxic amyloid-β fragments. Hence, inhibition of BACE1 was stated to be an effective strategy for Alzheimer's therapeutics. Keeping in mind the structures of different BACE1 inhibitors that had reached the clinical trials, we designed a library of compounds (total 164) based on a substituted 5-amino tetrazole scaffold which was an isosteric replacement of the cyclic amidine moiety, a common component of the BACE1 inhibitors which reached the clinical trials. The scaffold was linked to different structural moieties with the aid of an amide or sulfonamide bond to design some novel molecules. Molecular docking was initially performed and the top 5 molecules were selected based on docking scores and protein-ligand interactions. Furthermore, molecular dynamic simulations were performed for these molecules (3g, 7k, 8n, 9d, 9g) for 100 ns and MM-GBSA calculations were performed for each of these complexes. After critical evaluation of the obtained results, three potential molecules (9d, 8n, and 7k) were forwarded for prolonged stability studies by performing molecular dynamic simulations for 250 ns and simultaneous MM-GBSA calculations. It was observed that the compounds (9d, 8n, and 7k) were forming good interactions with the amino acid residues of the catalytic site of the enzyme with multiple non-covalent interactions. In MD simulations, the compounds have shown better stability and better binding energy throughout the runtime. Show less