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Multi-Target-Directed Ligand Approach in Anti-Alzheimer’s Drug Discovery

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Deciphering Drug Targets for Alzheimer’s Disease

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Abstract

Alzheimer’s disease is a multifactorial neurodegenerative syndrome and has raised concern related to global health and economy. Numerous targets have been analyzed toward discovery and development of potential therapeutics. Some of the single-target-based Food and Drug Administration (FDA) approved drugs include donepezil, galantamine, rivastigmine, and memantine which can improve the patient condition but fail to completely cure the disease. Single-target therapeutics have limitations to cure the disease due to complicated pathogenesis and complex network formed by the associated signaling pathways. Thus, the multi-target-directed ligand (MTDL) approach has gained importance as the potential anti-Alzheimer’s drugs having the advantages of synergistic effect with improved cognition and regulating its progression. In the present chapter, multi-target-directed approaches are discussed with coverage of design strategies and promising compounds reported in recent years. Some of the well-explored targets like acetylcholine esterase (AChE), ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3ß (GSK-3ß), monoamine oxidases (MAOs), metal ions in the brain, N-methyl-D-aspartate (NMDA) receptor, and phosphodiesterases (PDE) are described focusing on their contribution toward cognitive neurodegeneration leading to Alzheimer’s disease (AD).

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Abbreviations

5-HT:

5-Hydroxytryptamine

AChE:

Acetylcholine esterase

AChEI :

Acetylcholine esterase inhibitor

AD :

Alzheimer’s disease

APOE :

Apolipoprotein E

BACE!:

ß-site amyloid precursor protein-cleaving enzyme 1

BBB:

Blood–brain barrier

BuChE :

Butyrylcholinesterase

CB1:

Cannabinoid-based 1

ChAT :

Acetyltransferase

FDA:

Food and drug administration

GSK-3ß:

Glycogen synthase kinase 3ß

JNK :

c-Jun N-terminal kinase

MAO:

Monoamine oxidases

MTDL :

Multi-target-directed ligand

NFT :

Neurofibrillary tangles

NMDAR :

N-methyl-D-aspartate receptor,

NQO1:

NAD(P)H quinone oxidoreductase

PAMPA :

Parallel artificial membrane permeation assay

PDE :

Phosphodiesterase

ROCK :

Rho-associated protein kinase

ROS :

Reactive oxygen species

α-M:

α-Mangostin

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh, India

    Vaishali M. Patil

  2. Department of Pharmacy, Lala Lajpat Rai Memorial Medical College, Meerut, Uttar Pradesh, India

    Neeraj Masand

  3. Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India

    Vertika Gautam

  4. Department of Pharmaceutical Chemistry, KIET School of Pharmacy, KIET Group of Institutions, Ghaziabad, Uttar Pradesh, India

    Shikha Kaushik

  5. Department of Radiological Sciences, Section of Medical Physics, University of Oklahoma, Norman, OK, USA

    Dee Wu

  6. Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia

    Vaishali M. Patil

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  1. Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA

    Dileep Kumar

  2. Department of Pharmaceutical Chemistry, KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, Uttar Pradesh, India

    Vaishali M. Patil

  3. Department of Radiological Sciences, Section of Medical Physics, University of Oklahoma, Norman, OK, USA

    Dee Wu

  4. Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK

    Nanasaheb Thorat

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Patil, V.M., Masand, N., Gautam, V., Kaushik, S., Wu, D. (2023). Multi-Target-Directed Ligand Approach in Anti-Alzheimer’s Drug Discovery. In: Kumar, D., Patil, V.M., Wu, D., Thorat, N. (eds) Deciphering Drug Targets for Alzheimer’s Disease. Springer, Singapore. https://doi.org/10.1007/978-981-99-2657-2_13

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