Alzheimer's Disease and β-Secretase Inhibition: An Update With a Focus on Computer-Aided Inhibitor Design

2021 ◽  
Vol 22 ◽  
Author(s):  
Samuel Ugbaja ◽  
Isiaka Lawal ◽  
Hezekiel Kumalo ◽  
Monsurat Lawal
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Discovery ◽  
Inhibitor Design ◽  
Vitro Assay ◽  
Bace1 Inhibitor ◽  
In Silico Studies ◽  
Computer Aided

Introduction: Alzheimer's disease (AD) is an intensifying neurodegenerative illness due to its irreversible nature. Identification of β‐site amyloid precursor protein (APP) cleaving enzyme1 (BACE1) has been a significant medicinal focus towards AD treatment, and this has opened ground for several investigations. Despite the numerous works in this direction, no BACE1 inhibitor has made it to the final approval stage as an anti-AD drug. Method: We provide an introductory background of the subject with a general overview of the pathogenesis of AD. The review features BACE1 inhibitor design and development with a focus on some clinical trials and discontinued drugs. Using the topical keywords BACE1, inhibitor design, and computational/theoretical study in the Web of Science and Scopus database, we retrieved over 49 relevant articles. The search years are from 2010 and 2020, with analysis conducted from May 2020 to March 2021. Results and discussion: Researchers have employed computational methodologies to unravel potential BACE1 inhibitors with a significant outcome. The most used computer-aided approach in BACE1 inhibitor design and binding/interaction studies are pharmacophore development, quantitative structure-activity relationship (QSAR), virtual screening, docking, and molecular dynamics (MD) simulations. These methods, plus more advanced ones including quantum mechanics/molecular mechanics (QM/MM) and QM, have proven substantial in the computational framework for BACE1 inhibitor design. Computational chemists have embraced the incorporation of in vitro assay to provide insight into the inhibition performance of identified molecules with potential inhibition towards BACE1. Significant IC50 values up to 50 nM, better than clinical trial compounds, are available in the literature. Conclusion: The continuous failure of potent BACE1 inhibitors at clinical trials is attracting many queries prompting researchers to investigate newer concepts necessary for effective inhibitor design. The considered properties for efficient BACE1 inhibitor design seem enormous and require thorough scrutiny. Lately, researchers noticed that besides appreciable binding affinity and blood-brain barrier (BBB) permeation, BACE1 inhibitor must show low or no affinity for permeability-glycoprotein. Computational modeling methods have profound applications in drug discovery strategy. With the volume of recent in silico studies on BACE1 inhibition, the prospect of identifying potent molecules that would reach the approved level is feasible. Investigators should try pushing many of the identified BACE1 compounds with significant anti-AD properties to preclinical and clinical trial stages. We also advise computational research on allosteric inhibitor design, exosite modeling, and multisite inhibition of BACE1. These alternatives might be a solution to BACE1 drug discovery in AD therapy.

scholarly journals Integrating Biomarker Outcomes into Clinical Trials for Alzheimer’s Disease in Down Syndrome

2020 ◽  
pp. 1-4 ◽  
Author(s):  
M.S. Rafii ◽  
S. Zaman ◽  
B.L. Handen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Down Syndrome ◽  
Natural History ◽  
New Information ◽  
History Of ◽  
Clinically Meaningful Outcomes

The NIH-funded Alzheimer’s Biomarker Consortium Down Syndrome (ABC-DS) and the European Horizon 21 Consortium are collecting critical new information on the natural history of Alzheimer’s Disease (AD) biomarkers in adults with Down syndrome (DS), a population genetically predisposed to developing AD. These studies are also providing key insights into which biomarkers best represent clinically meaningful outcomes that are most feasible in clinical trials. This paper considers how these data can be integrated in clinical trials for individuals with DS. The Alzheimer’s Clinical Trial Consortium - Down syndrome (ACTC-DS) is a platform that brings expert researchers from both networks together to conduct clinical trials for AD in DS across international sites while building on their expertise and experience.

scholarly journals Rapamycin and Alzheimer’s disease: Time for a clinical trial?

2019 ◽  
Vol 11 (476) ◽  
pp. eaar4289 ◽  
Author(s):  
Matt Kaeberlein ◽  
Veronica Galvan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Animal Models ◽  
Mouse Models ◽  
Mtor Inhibitors ◽  
Beneficial Effects

The drug rapamycin has beneficial effects in a number of animal models of neurodegeneration and aging including mouse models of Alzheimer’s disease. Despite its compelling preclinical record, no clinical trials have tested rapamycin or other mTOR inhibitors in patients with Alzheimer’s disease. We argue that such clinical trials should be undertaken.

scholarly journals Alzheimer’s Disease Neuropathological Comorbidities Are Common in the Younger-Old

2020 ◽  
Author(s):  
Thomas G. Beach ◽  
Michael Malek-Ahmadi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Response ◽  
Oldest Old ◽  
Diagnostic Methods ◽  
Lower Probability ◽  
Molecular Therapeutics

AbstractClinicopathological studies have demonstrated that Alzheimer’s disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the presence and rate of cognitive decline in aging and ADD. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown. We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer’s Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer’s Association (NIA-AA) intermediate or high AD Neuropathological Change (ADNC) levels, excluding those with known autosomal dominant AD-related mutations. Subjects were divided into age-at-death categories for analysis: under 60, 60-69, 70-79, 80-89, 90-99 and 100 or over. Confirmatory of earlier reports, ADD histopathology is less severe with advancing age, effectively increasing the relative contribution of comorbidities, most of which rise in prevalence with age. Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where “pure” ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20% in the 70s and beyond. Comorbidity rates for some pathologies, especially LBD, are high even in subjects in their 60s and 70s, at nearly 60%, but for most others, their prevalence increases with age. TDP-43 pathology affects more than 35% of ADD subjects 80 and over while microscopic infarcts reach this rate a decade later. Gross infarcts rise more slowly and affect fewer subjects but still involve 15-20% of ADD after age 80. White matter rarefaction may be underestimated in the NACC database but is present in almost 70% of centenarians with ADD. Effective clinical trials depend on accurate estimates of required subject numbers, which are dependent on observed effect size and clinical response variability. Comorbidities are likely to affect both, leading to lower probability of clinical trial success. Stratifying ADD clinical trial analyses by presence and types of accompanying comorbidities might identify subgroups with higher effect sizes and greater clinical response rates, but accurate in-vivo diagnostic methods for most comorbidities are still lacking.

scholarly journals (-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer’s Disease

2018 ◽  
Vol 15 (9) ◽  
pp. 883-891 ◽  
Author(s):  
Robert E. Becker ◽  
Nigel H. Greig ◽  
Debomoy K. Lahiri ◽  
Joseph Bledsoe ◽  
Sarah Majercik ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Cell Death ◽  
Animal Models ◽  
Programmed Cell Death ◽  
Release Formulation ◽  
Amyloid Hypothesis ◽  
Moderate Traumatic Brain Injury

Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate’s potential for preventing PPCD and resulting progression towards dementia in AD. Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment' Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.

scholarly journals Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer’s Disease Therapeutic Agents

Marine Drugs ◽  
2017 ◽  
Vol 15 (12) ◽  
pp. 366 ◽  
Author(s):  
Laura Llorach-Pares ◽  
Alfons Nonell-Canals ◽  
Melchor Sanchez-Martinez ◽  
Conxita Avila
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Drug Design ◽  
Therapeutic Agents ◽  
Computer Aided Drug Design ◽  
Computer Aided

Clinical Global Impressions in Alzheimer's Clinical Trials

1996 ◽  
Vol 8 (2) ◽  
pp. 277-290 ◽  
Author(s):  
Lon S. Schneider ◽  
Jason T. Olin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Global Impression ◽  
Treatment Effects ◽  
Global Rating ◽  
Cooperative Study ◽  
History Of ◽  
Global Impression Of Change

This article reviews the history of Clinical Global Impressions of Change (CGIC) instruments, their use and limitations in clinical trials of Alzheimer's disease, and the development of the National Institute on Aging's Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale (ADCS-CGIC). Originally, CGICs were simple and unstructured instruments that asked a clinician to rate change over the duration of a clinical trial. The method, however, failed to consistently detect treatment effects, leading to the development of more structured and subsequently validated approaches, such as the Clinician Interview-Based Impression Scale (CIBI) and the ADCS-CGIC. Both are currently used in clinical trials. The implications and importance of choosing an appropriate global rating are discussed.

In-silico studies and Biological activity of potential BACE-1 Inhibitors

2020 ◽  
Vol 23 ◽  
Author(s):  
Richa Arya ◽  
Sarvesh Paliwal ◽  
S.P Gupta ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activity ◽  
In Silico ◽  
Neuronal Damage ◽  
Pharmacophore Model ◽  
Vitro Assay ◽  
App Processing ◽  
In Silico Studies ◽  
Bace 1

Background: Alzheimer’s disease is neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in brain is caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP). Objective: : The controlled APP processing by inhibition of secretase is the strategy to reduce Aβ load to treat Alzheimer’s disease. Method: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with activity magnitude of greater than 4.of compounds. Results: In an advent to design new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by in-silico approach were evaluated by docking interactions. Conclusion: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl substituted carbamate compound exhibited highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1µM.

Utility of Clinical Trial Batteries in the Measurement of Alzheimer's and Huntington's Dementia

1996 ◽  
Vol 8 (3) ◽  
pp. 397-411 ◽  
Author(s):  
Erich Mohr ◽  
Denise Walker ◽  
Christopher Randolph ◽  
Margaret Sampson ◽  
Tilak Mendis
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Outcome Measures ◽  
Rating Scale ◽  
Normal Subjects ◽  
Assessment System ◽  
Disease Assessment ◽  
Mild Dementia

Tests used as outcome measures in clinical trials of antidementia agents are not typically employed as part of diagnostic evaluations, and little information exists as to the sensitivity of these tests in terms of either differentiating demented patients from normal individuals or in distinguishing dementias of various types and etiologies. Sensitivity to mild dementia and sensitivity to impairment of various neuropsychological domains are, however, prerequisites for valid use of an instrument as an outcome measure in this context. The present study was undertaken to directly compare six different tests (three traditional psychometric tests and three clinical trial batteries) in terms of their sensitivity to detect and distinguish between mild dementia in patients with either Alzheimer's disease (n = 15) or Huntington's disease (n = 15), when compared to normal controls (n = 15). Tests included the Mattis Dementia Rating Scale, the Mini-Mental State Examination, the Wechsler Memory Scale-Revised, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Computerized Drug Research (CDR) Cognitive Assessment System, and the Repeatable Battery for the Assessment of Dementia (RBAD). All of the tests were roughly equivalent in terms of their ability to discriminate normal subjects from mildly demented patients. Only the CDR and RBAD, however, were able to reliably discriminate between the two patient groups. The results are discussed in terms of the applicability of these tests as outcome measures for clinical trials in dementing disorders.

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