Treffer: Breaking barriers: Medicinal chemistry strategies and advanced in-silico approaches for overcoming the BBB and enhancing CNS penetration.

Title:
Breaking barriers: Medicinal chemistry strategies and advanced in-silico approaches for overcoming the BBB and enhancing CNS penetration.
Authors:
Ajayi ED; Irma Lerma Rangel School of Pharmacy, Texas A&M, University, College Station, TX, 77843, USA., Elazazy M; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt., Abouzid K; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt., Ali HI; Irma Lerma Rangel School of Pharmacy, Texas A&M, University, College Station, TX, 77843, USA. Electronic address: alyismail@tamu.edu.
Source:
European journal of medicinal chemistry [Eur J Med Chem] 2026 Jan 05; Vol. 301, pp. 118219. Date of Electronic Publication: 2025 Sep 30.
Publication Type:
Journal Article; Review
Language:
English
Journal Info:
Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
Imprint Name(s):
Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
MeSH Terms:
Blood-Brain Barrier*/metabolism , Blood-Brain Barrier*/drug effects , Central Nervous System*/metabolism , Central Nervous System*/drug effects , Central Nervous System Agents*/chemistry , Central Nervous System Agents*/pharmacology , Computer Simulation* , Small Molecule Libraries*/chemistry , Small Molecule Libraries*/pharmacology, Humans ; Chemistry, Pharmaceutical ; Animals
Contributed Indexing:
Keywords: Blood-brain barrier (BBB); Central nervous system (CNS); Drug delivery; Machine learning; Small Molecule
Substance Nomenclature:
0 (Central Nervous System Agents)
0 (Small Molecule Libraries)
Entry Date(s):
Date Created: 20251008 Date Completed: 20251113 Latest Revision: 20251114
Update Code:
20251114
DOI:
10.1016/j.ejmech.2025.118219
PMID:
41061295
Database:
MEDLINE

Weitere Informationen

Delivering small molecules to the brain and central nervous system (CNS) is greatly hindered by the restrictive blood-brain barrier (BBB), which selectively permits essential molecules while excluding toxic molecules. This selective permeability feature of the membrane also poses a challenge in delivering small molecules to the brain intended for therapeutic benefits. Pharmaceutical approaches such as designing a prodrug, conjugating with liposomes/immunoliposomes, and formulating as nanoparticles have been employed to increase BBB penetration. Despite these efforts, the challenge of suboptimal concentration reaching the brain persists. Modifying small molecules in the early stages of drug discovery is a promising strategy for designing drugs that can penetrate the BBB. To achieve this, it is essential to fine-tune physicochemical parameters to enhance permeability while carefully avoiding toxicity. In this review, we elucidate the most recent strategies for optimizing small molecules by adjusting molecular weight, lipophilicity, pKa, number of hydrogen bond donors, number of rotatable bonds, topological polar surface area, and the ratio of drug concentration in the brain to that in the blood (LogBB). This review will enable researchers to rapidly adopt a framework to overcome BBB challenges in CNS drug discovery by integrating empirical and computational strategies. The insights presented here aim to empower researchers to develop effective BBB-penetrable small molecules, advancing CNS therapeutics and improving the treatment of neurological disorders and brain metastasis.
(Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hamed I. Ali reports financial support was provided by Texas A&M University. N/A If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.