Breaking Barriers: Medicinal Chemistry Strategies and Advanced In-Silico Approaches for Overcoming the BBB and Enhancing CNS Penetration

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.