Challenges in Alzheimer’s Disease Drug Discovery and Development: The Role of Modeling, Simulation, and Open Data
Abstract
Alzheimer's disease (AD) is the leading cause of dementia worldwide. With 35 million people over 60 years of age with dementia, there is an urgent need to develop new treatments for AD. To streamline this process, it is imperative to apply insights and learnings from past failures to future drug development programs. In the present work, we focus on how modeling and simulation tools can leverage open data to address drug development challenges in AD.
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The BBB is impermeable to 98% of small molecules and around 100% of large molecules in relevant quantities.
“The BBB is impermeable to 98% of small molecules and around 100% of large molecules in relevant quantities.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [193]
Candidates for BBB penetration are characterized by molecular weight less than 450 Daltons, polar surface area less than 90 Å2, and hydrogen bond donor number less than 3.
“A molecular weight less than 450 Daltons, a polar surface area less than 90 Å2, and a hydrogen bond donor number less than 3 are characteristics of candidates for BBB penetration.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [193]
The indicated BBB penetration values are inconsistent with the physicochemical characteristics of monoclonal antibodies (solanezumab, aducanumab, bapineuzumab) or gamma-secretase inhibitors (semagacestat, tarenflurbil).
“The indicated BBB penetration values are inconsistent with the physicochemical characteristics of monoclonal antibodies (solanezumab, aducanumab, bapineuzumab) or gamma-secretase inhibitors (semagacestat, tarenflurbil) [193,194,195].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [193]
For a medicine to penetrate the BBB, its physicochemical properties-polar surface area, molecular weight, and lipophilicity as assessed by hydrogen bonding ability-are essential.
“For a medicine to penetrate the blood–brain barrier, its physicochemical properties—such as its polar surface area, molecular weight, and lipophilicity as assessed by hydrogen bonding ability—are essential.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [193]
The blood-brain barrier (BBB) is an important impediment to the development of AD medications because it prevents potential drug candidates from entering the brain parenchyma.
“An important impediment to the development of AD medications is the blood–brain barrier (BBB), which prevents potential drug candidates from entering the brain parenchyma.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [193]
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References 89 · Cited by 21
- Authors
- Conrado, D. J., Duvvuri, S., Geerts, H., Burton, J., Biesdorf, C., Ahamadi, M., Macha, S., Hather, G., Francisco Morales, J., Podichetty, J., Nicholas, T., Stephenson, D., Trame, M., Romero, K., Corrigan, B., & the Drug Development Tools in the Alzheimer Disease Continuum (DDT‐AD) Working Group
- Affiliations
- e‐Quantify La Jolla California USA
- Cerevel Therapeutics (United States) (US)
- In Silico Biosciences (United States) (US)
- Critical Path Institute (US)
- Indiana University Indianapolis (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Sanofi (United States) (US)
- Takeda La Jolla California USA
- Laboratorio de Investigación y Desarrollo de Bioactivos (LIDeB) Faculty of Exact Sciences, National University of La Plata (UNLP) Buenos Aires Argentina
- Pfizer (United States) (US)
- Novartis Cambridge Massachusetts USA
- Corresponding author
- Conrado, Daniela J.
- ORCID
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2020-03-11
- Volume
- 107
- Issue
- 4
- Pages
- 796-805
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- OpenAlex
- W2999083560
- Cited by
- 21
- References
- 89
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 3
- FWCI
- 0.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Food and Drug Administration (U18FD005320)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- Alzheimer's disease, drug discovery, drug development, modeling and simulation, open data, dementia, translational research, drug development failure
- MeSH terms
- Drug Development, Alzheimer Disease, Animals, Clinical Trials as Topic, Computer Simulation, Data Collection, Humans, Drug Discovery, Translational Research, Biomedical
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