Computational Modeling of Pharmaceuticals with an Emphasis on Crossing the Blood–Brain Barrier

The discovery and development of new pharmaceutical drugs is a costly, time-consuming, and highly manual process, with significant challenges in ensuring drug bioavailability at target sites. Computational techniques are highly employed in drug design, particularly to predict the pharmacokinetic properties of molecules. One major kinetic challenge in central nervous system drug development is the permeation through the blood–brain barrier (BBB). Several different computational techniques are used to evaluate both BBB permeability and target delivery. Methods such as quantitative structure–activity relationships, machine learning models, molecular dynamics simulations, end-point free energy calculations, or transporter models have pros and cons for drug development, all contributing to a better understanding of a specific characteristic. Additionally, the design (assisted or not by computers) of prodrug and nanoparticle-based drug delivery systems can enhance BBB permeability by leveraging enzymatic activation and transporter-mediated uptake. Neuroactive peptide computational development is also a relevant field in drug design, since biopharmaceuticals are on the edge of drug discovery. By integrating these computational and formulation-based strategies, researchers can enhance the rational design of BBB-permeable drugs while minimizing off-target effects. This review is valuable for understanding BBB selectivity principles and the latest in silico and nanotechnological approaches for improving CNS drug delivery.