Abstract
Successful drug administration to the central nervous system requires accurate adjustment of the drugs’ molecular properties. Therefore, structure-derived descriptors of potential brain therapeutic agents are essential for an early evaluation of pharmacokinetics during drug development. The collision cross section (CCS) of molecules was recently introduced as a novel measurable parameter to describe blood-brain barrier (BBB) permeation. This descriptor combines molecular information about mass, structure, volume, branching and flexibility. As these chemical properties are known to influence cerebral pharmacokinetics, CCS determination of new drug candidates may provide important additional spatial information to support existing models of BBB penetration of drugs. Besides measuring CCS, calculation is also possible; but however, the reliability of computed CCS values for an evaluation of BBB permeation has not yet been fully investigated. In this work, prediction tools based on machine learning were used to compute CCS values of a large number of compounds listed in drug libraries as negative or positive with respect to brain penetration (BBB+ and BBB− compounds). Statistical evaluation of computed CCS and several other descriptors could prove the high value of CCS. Further, CCS-deduced maximum molecular size of BBB+ drugs matched the dimensions of BBB pores. A threshold for transcellular penetration and possible permeation through pore-like openings of cellular tight-junctions is suggested. In sum, CCS evaluation with modern in silico tools shows high potential for its use in the drug development process.
Highlights
Accepted: 8 December 2021Successful brain therapy places high demands on the molecular properties of drugs.Besides activity towards cerebral target sites, appropriate cerebral pharmacokinetics (PK)are essential
According to the batch prediction instructions given on this website, following the example .csv file), Simplified Molecular Input Line Entry Specification (SMILES) codes of the substances were uploaded as a .csv file and predictions were conducted
As is shown in this work, the unambiguous SMILES code of a molecule allows the calculation of its collision cross section (CCS) and a subsequent prediction of possible brain penetration
Summary
Accepted: 8 December 2021Successful brain therapy places high demands on the molecular properties of drugs.Besides activity towards cerebral target sites, appropriate cerebral pharmacokinetics (PK)are essential. Successful brain therapy places high demands on the molecular properties of drugs. Besides activity towards cerebral target sites, appropriate cerebral pharmacokinetics (PK). Most drugs do not sufficiently reach the brain [1,2]. A primary obstacle drugs must overcome to enter the central nervous system (CNS) is the blood-brain barrier (BBB), a complex protective shield, built up first of all of endothelial cells at the epithelium of the vascular network of the brain [3,4]. The neurovascular unit is composed of endothelial cells, a basal lamina, pericytes and astrocytes, the latter of which are relevant in inducing and maintaining the barrier function and linking to neurons [6]
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