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Giulia Caron

University of Torino, Italy

Title: The Block Relevance (BR) analysis to interpret chromatographic data: application to IAM chromatography in permeability studies

Biography

Biography: Giulia Caron

Abstract

Statement of the Problem: The Block Relevance (BR) analysis is a computational tool that can be conveniently used to characterize and compare chromatographic scales. Immobilised Artificial Membranes (IAM) chromatography is expected to predict drug membrane permeability, a pivotal molecular property in drug discovery processes. The purpose of this study is to extract by BR analysis the balance of intermolecular interactions governing IAM descriptors (log KwIAM, log KwIAM) and verify their relationship with passive permeability. Methodology: Experimental: The RP-HPLC analyses were performed with 20 mM ammonium/acetate at pH 7.0 in water or in mixture with acetonitrile at various percentages. The stationary phase was IAM.PC.DD.2: its surface is formed by covalently bonding the membrane forming phospholipids to silica (Regis, 10cmx4.6cm 10um packing 300Å pore size). The flow rate was 1.0 ml/min. Computational: VolSurf+ (Vs+) software (version 1.0.7, http://www.moldiscovery.com) was used to generate PLS models with default settings and four probes (OH2, DRY, N1, and O probes that mimic, respectively, water, hydrophobic, HBA, and HBD properties of the environment). BR analysis was performed using an in-house software. Findings: BR analysis showed that 

successful prediction of permeability using log KwIAM alone is unlikely to occur but its combination with PSA can reasonably well predict PAMPA log Peff of neutral and ionized compounds. Conversely, log KwIAM is a polarity descriptor and thus plays a very relevant role in the prediction of cellular permeability Conclusion: IAM chromatography provides two descriptors (log KwIAM and log KwIAM) of interest in the prediction of permeability, which is a crucial issue of any drug discovery project. Overall, this study highlights that, prior to their application to biological/toxicological topics, any chromatographic descriptor should be characterized for its information content using a tool like BR analysis.