BITS Faculty Publications
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Item Identification of Azelastine and Carvedilol as Cholinesterase Inhibitors via Structure-Based Virtual Screening of FDA-approved Drugs(Wiley, 2023-07) Jadhav, Hemant R.The structure-based virtual screening (SBVS) has gained immense importance in early drug discovery. Herein, we report the SBVS-driven identification of new cholinesterase inhibitors from a library of FDA-approved small molecule drugs (n=1760). The in vitro validation of top SBVS hits provided azelastine, dronedarone, and iloperidone as acetylcholinesterase (AChE) inhibitors with IC50 values of 9.2, 18.2, and 23.0 μM, respectively. The in vitro screening of top actives in the butyrylcholinesterase (BChE) inhibition assay provided carvedilol as a potent BChE inhibitor with an IC50 of 0.8 μM. Azelastine also inhibits BChE with IC50 of 4.89 μM, indicating its dual ChE inhibition activity. Azelastine and carvedilol also inhibit the self-aggregation of Aβ1–42 with IC50 values of 4.6 and 2.2 μM, respectively. Both drugs cross blood-brain barrier (BBB), as indicated by the parallel artificial membrane permeation assay. Results presented herein warrant exploring the repurposing potential of azelastine and carvedilol for Alzheimer's disease.Item Design, Synthesis and Evaluation of 2,4,6-substituted Pyrimidine Derivatives as BACE-1 Inhibitor: Plausible Lead for Alzheimer’s Disease(Bentham Science, 2021) Jadhav, Hemant R.Alzheimer’s disease is one of the most common neurodegenerative disorder afflicting a large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway considered responsible for Alzheimer’s disease (AD). Since it catalyzes the rate-limiting step of Aβ-42 production from amyloid precursor protein (APP), its inhibition is considered a viable therapeutic strategy. We have reported the design of small molecular weight compounds supposed to be blood brain permeable as BACE-1 inhibitors. The clue for the design of this series is drawn from the previously designed series from our research group.Item Therapeutic Advances in the Treatment of Alzheimer's Disease: Present and Future(Bentham Science, 2011-11) Jadhav, Hemant R.The underlying pathogenesis of Alzheimer's disease (AD) is complex and is still under exploration. This has hampered the attempts to design highly selective and potent agents to treat AD. This review summarizes the present status of AD, present strategies and hypotheses (with underlying upstream and downstream events) for designing new drugs for AD. It also appraises the drugs based on present strategies that are in various stages of clinical trials, failures and the reasons for their failure. Further, it describes the future strategies being adopted for the anti-alzheimer's drug design. The recent approaches like immunotherapy, multi-targeted drug ligand design, usage of electromagnetic radiation and nanoparticle-mediated drug delivery are upcoming tools to overcome the impediment and have been discussed in this review.Item Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors(Bentham Science, 2020) Jadhav, Hemant R.Glycogen Synthase Kinase 3 (GSK3) is one of the Serine/Threonine protein kinases, which has gained a lot of attention for its role in a variety of pathways. It has two isoforms, GSK3α and GSK3β. However, GSK3β is highly expressed in different areas of the brain and has been implicated in Alzheimer’s disease as it is involved in tau phosphorylation. Due to its high specificity concerning substrate recognition, GSK3 has been considered as an important target. In the last decade, several GSK3 inhibitors have been reported and two molecules are in clinical trials. This review collates the information published in the last decade about the role of GSK3 in Alzheimer’s disease and progress in the development of its inhibitors. Using this collated information, medicinal chemists can strategize and design novel GSK3 inhibitors that could be useful in the treatment of Alzheimer’s disease.