520A robust numerical algorithm to computationally predict the ability of drug molecules to cross the blood-brain barrier (BBB) is of relevance to basic neuroscience and to the pharmacology of drug design. [1][2][3][4] A molecule can cross the BBB by either active transport or passive diffusion; 4 passive diffusion remains the most important method for the greatest structural diversity of drug molecules. The two most widely recognized principal physical properties that influence passive diffusion across the BBB (with subsequent entry into the brain) are molecular size and lipophilicity. [4][5][6][7] Although equations that quantitatively relate trans-BBB diffusion to these two properties have been proposed, [8][9][10] these models use only one predictor to encode each of the factors of size and lipophilicity.This study endeavours to develop a rigorous theoretical ABSTRACT: Background: Predicting the ability of drugs to enter the brain is a longstanding problem in neuropharmacology. The first step in creating a much-needed computational algorithm for predicting whether a drug will enter brain is to devise a rigorous mathematical model. Methods: Employing two experimental measures of blood-brain barrier (BBB) penetrability (brain/plasma ratio and the brainuptake index) and 14 theoretically derived biophysical predictors, a mathematical model was developed to quantitatively correlate molecular structure with ability to traverse the BBB. Results: This mathematical model employs Stein's hydrogen bonding number and Randic's topological descriptors to correlate structure with ability to cross the BBB. The final model accurately predicts the ability of test molecules to cross the BBB. Conclusions: A mathematical method to predict blood-brain barrier penetrability of drug molecules has been successfully devised. As a result of bioinformatics, chemoinformatics and other informatics-based technologies, the number of small molecules being developed as potential therapeutics is increasing exponentially. A biophysically rigorous method to predict BBB penetrability will be a much-needed tool for the evaluation of these molecules.RÉSUMÉ: Un modèle mathématique pour prédire la diffusion de molécules à travers la barrière hémato-encéphalique. Introduction : En neuropharmacologie, il est difficile de prédire quels médicaments pourront pénétrer dans le cerveau. La première étape dans la création d'un algorithme pour prédire si un médicament pénétrera dans le cerveau est d'élaborer un modèle mathématique rigoureux. Méthodes : Un modèle mathématique a été développé en utilisant deux mesures expérimentales de la perméabilité de la barrière hémato-encéphalique (BHE) [le ratio cerveau/plasma (RCP) et l'indice de captation du cerveau (ICC)] et 14 prédicteurs biophysiques théoriques, afin de corréler quantitativement la structure moléculaire d'une substance et sa capacité à pénétrer la BHE. Ce modèle mathématique utilise le nombre de liaisons hydrogène de Stein et les indices topologiques de Randic pour corréler la structure de la molécul...
