Chemometric Analysis to Probe Blood Brain Barrier Permeability of New Chemical Entities (NCEs)

Abstract

In present world one of greatest challenges faced by pharmaceutical industry is to maximize efficacy of various neuroactive agents and minimize the risk of neurotoxicity of drugs designed for peripheral body systems. Bioavailability of a neuroactive active agent depends upon its transport across blood brain barrier and thus, is a factor of vital importance in determining drug efficacy. Over the past few decades, intensive research efforts have been made to elucidate blood brain barrier permeability of compounds. However, these experiments are very costly and time demanding endeavors. Therefore, in this study various chemometeric models, including Principal Component Analysis (PCA) and Partial Least Square Analysis (PLS) using Grid Independent Descriptors have been developed to predict blood brain barrier permeability of a diverse dataset of 218 compounds. Our model elucidates two hydrogen bond donor groups at a mutual distance of 6.00 Å to 6.40 Å and a hydrophobic group at a mutual distance of 10 Å to 10.4 Å from one of the hydrogen bond donor groups may have a positive impact on blood brain barrier permeability of already marketed neuroactive agents. Overall, this study can prove to be useful for prediction of blood brain barrier permeability of new chemical entities in early stages of drug development.