CΔlog kw IAM: can we afford estimation of small molecules' blood-brain barrier passage based upon in silico phospholipophilicity?

Lucia Grumetto,Giacomo Russo

doi:10.5599/admet.1034

Lucia Grumetto, Giacomo Russo

Open Access

https://doi.org/10.5599/admet.1034

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Abstract

56 compounds, whose log BB values were known from the scientific literature, were considered and their phospholipophilicity values were calculated in silico. These values, along with either experimentally determined or calculated lipophilicity values, were used to extract cΔ/Δ’log kwIAM parameters. cΔ/Δ’log kwIAM values were found inversely related to data of blood-brain barrier passage, especially in the < -0.20 log BB range and on the IAM.PC.DD2 phase (r2 = 0.79). In multiple linear regression, satisfactory statistic models (r2 (n-1) = 0.76), based on cΔ/Δ’log kwIAM.MG along with other in silico calculated descriptors, were achieved. This method brings the potential to be applied, along with other methodologies, to filter out solutes whose BBB permeation is foreseen to be substandard, thus allowing pharmaceutical companies/research institutes to focus on candidates that are more likely to concentrate in the brain.

Highlights

Combinatorial chemistry involves the generation of a large array of structurally diverse compounds, i.e., a chemical library, through systematic, repetitive and covalent linkage of various “building blocks” [1]
Back in 2017, we developed some statistical models to predict the phospholipophilicity of small molecules based on more than 200 individual measurements performed in our laboratories
C / ’log kwIAM values calculation c / ’log kwIAM values were calculated from phospholipophilicity values estimated in silico according to a procedure we developed in 2017 [24]

Summary

Introduction

Combinatorial chemistry involves the generation of a large array of structurally diverse compounds, i.e., a chemical library, through systematic, repetitive and covalent linkage of various “building blocks” [1]. This technique can be exploited in parallel, delivering hundreds, if not thousands, of molecules of pharmaceutical interest in a handful of hours. Most of the testing still requires animal models that have the undeniable advantage of mirroring more closely the complexity of human beings than cells. Animal models are facing criticism from the public since they often require the sacrifice of vertebrates [3] and heavily impact the environment due to the huge number of carcasses to dispose of.

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