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Recent Drug Design Strategy of the Design of Molecules against Alzheimer’s Disease and Parkinson’s Disease

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 9320

Special Issue Editors

Dr. Bijo Mathew

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India
Interests: drug discovery of neurodegenerative disorders; cancer and molecular modelling
Prof. Dr. Orazio Nicolotti

E-Mail Website
Guest Editor
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Bari, Italy
Interests: computer-aided drug design; predictive toxicology; chemoinformatics; artificial intelligence; digital platforms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most prevalent of the heterogeneous and complex neurodegenerative disorders (NDDs) that largely affect the elderly patients. Their pathogenesis has been attributed to a variety of genomic, epigenomic, and environmental factors. Mounting evidence indicates that drugs targeting a single pathway cannot adequately address the multifactorial nature of NDDs. Oxidative stress, mitochondrial dysfunction, and imbalances in the levels of enzymes that control the metabolism of biogenic amines may promote NDD progression. On the other hand, several molecular scaffolds have been designed to simultaneously target entities such as choline esterase (ChE), monoamine oxidases (MAOs), and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE-1), to retard NDD progression.

Topics to be covered include the following:

  • Multi-target design of the molecules for AD;
  • Multi-target design of the molecules for PD;
  • Natural isolates for AD and PD;
  • Synthesis and Biological evaluation for the treatment of AD and PD.

Dr. Bijo Mathew
Prof. Dr. Orazio Nicolotti
Guest Editors

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Keywords

  • Alzheimer’s disease
  • Parkinson’s disease
  • choline esterase
  • monoamine oxidases
  • β-site amyloid precursor
  • β-secretase

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Published Papers (3 papers)

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Research

28 pages, 9351 KiB  
Article
Development of Activity Rules and Chemical Fragment Design for In Silico Discovery of AChE and BACE1 Dual Inhibitors against Alzheimer’s Disease
by Le-Quang Bao, Daniel Baecker, Do Thi Mai Dung, Nguyen Phuong Nhung, Nguyen Thi Thuan, Phuong Linh Nguyen, Phan Thi Phuong Dung, Tran Thi Lan Huong, Bakhtiyor Rasulev, Gerardo M. Casanola-Martin, Nguyen-Hai Nam and Hai Pham-The
Molecules 2023, 28(8), 3588; https://doi.org/10.3390/molecules28083588 - 20 Apr 2023
Cited by 4 | Viewed by 3105
Abstract
Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer’s disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of [...] Read more.
Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer’s disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and β-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD. Full article
(This article belongs to the Special Issue Recent Drug Design Strategy of the Design of Molecules against Alzheimer’s Disease and Parkinson’s Disease)
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12 pages, 2494 KiB  
Article
Development of [124/125I]IAZA as a New Proteinopathy Imaging Agent for Alzheimer’s Disease
by Thrisha T. Reddy, Michael H. Iguban, Lusine L. Melkonyan, Jasmine Shergill, Christopher Liang and Jogeshwar Mukherjee
Molecules 2023, 28(2), 865; https://doi.org/10.3390/molecules28020865 - 15 Jan 2023
Cited by 5 | Viewed by 2390
Abstract
Radioiodinated imaging agents for Aβ amyloid plaque imaging in Alzheimer’s disease (AD) patients have not been actively pursued. Our previous studies employed the “diaza” derivatives [11C]TAZA and [18F]flotaza in order to develop successful positron emission tomography (PET) imaging agents [...] Read more.
Radioiodinated imaging agents for Aβ amyloid plaque imaging in Alzheimer’s disease (AD) patients have not been actively pursued. Our previous studies employed the “diaza” derivatives [11C]TAZA and [18F]flotaza in order to develop successful positron emission tomography (PET) imaging agents for Aβ plaques. There is a need for radioiodinated imaging agents for Aβ plaques for single photon emission computed tomography (SPECT) and PET imaging. We report our findings on the preparation of [124/125I]IAZA, a “diaza” analog of [11C]TAZA and [18F]flotaza, and the evaluation of binding to Aβ plaques in the postmortem human AD brain. The binding affinity of IAZA for Aβ plaques was Ki = 10.9 nM with weak binding affinity for neurofibrillary tangles (Ki = 3.71 μM). Both [125I]IAZA and [124I]IAZA were produced in >25% radiochemical yield and >90% radiochemical purity. In vitro binding of [125I]IAZA and [124I]IAZA in postmortem human AD brains was higher in gray matter containing Aβ plaques compared to white matter (ratio of gray to white matter was >7). Anti-Aβ immunostaining strongly correlated with [124/125I]IAZA in postmortem AD human brains. The binding of [124/125I]IAZA in postmortem human AD brains was displaced by the known Aβ plaque imaging agents. Thus, radiolabeled [124/123I]IAZA may potentially be a useful PET or SPECT radioligand for Aβ plaques in brain imaging studies. Full article
(This article belongs to the Special Issue Recent Drug Design Strategy of the Design of Molecules against Alzheimer’s Disease and Parkinson’s Disease)
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12 pages, 1921 KiB  
Article
Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors
by Anusree Venkidath, Jong Min Oh, Sanal Dev, Elham Amin, Shebina P. Rasheed, Ajeesh Vengamthodi, Nicola Gambacorta, Ahmed Khames, Mohamed A. Abdelgawad, Ginson George, Orazio Nicolotti, Hoon Kim and Bijo Mathew
Molecules 2021, 26(19), 6004; https://doi.org/10.3390/molecules26196004 - 3 Oct 2021
Cited by 7 | Viewed by 2483
Abstract
A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent [...] Read more.
A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders. Full article
(This article belongs to the Special Issue Recent Drug Design Strategy of the Design of Molecules against Alzheimer’s Disease and Parkinson’s Disease)
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