In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

Klara Livia Valko,Charles Pidgeon,Simon P Teague

doi:10.5599/admet.5.1.373

Klara Livia Valko, Charles Pidgeon + Show 1 more

Open Access

https://doi.org/10.5599/admet.5.1.373

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Journal: ADMET & DMPK	Publication Date: Mar 24, 2017
Citations: 20	License type: cc-by

Affiliation: Regis Technologies (United States)

Abstract

<p class="ADMETabstracttext">The drug discovery process can be accelerated by chromatographic profiling of the analogs to model in vivo distribution and the major non-specific binding. A balanced potency and chromatographically determined membrane and protein binding (IAM MB/PB) data enable selecting drug discovery compounds for further analysis that have the highest probability to show the desired in vivo distribution behavior for efficacy and reduced chance for toxicity. Although the basic principles of the technology have already appeared in numerous publications, the lack of standardized procedures limited its widespread applications especially in academia and small drug discovery biotech companies. In this paper, the standardized procedures are described that has been trademarked as Regis IAM MB/PB Technology®. Comparison between the Drug Efficiency Index (DEI=pIC50-logVdu+2) and generally used Ligand Lipophilicity Efficiency (LLE) has been made, demonstrating the advantage of measured IAM and HSA binding over calculated log P. The power of the proposed chromatographic technology is demonstrated using the data of marketed drugs.</p>

Highlights

Medicinal chemists face multi-factorial challenge problems when designing drug molecules that can reduce the impact or cure a pathological condition; drug discovery scientists seek the smallest possible dose with minimal side effects [1,2,3,4]
Valko et al [51] highlighted that the maximum achievable drug efficiency (DEmax) that can be obtained assuming (i) 100 % bioavailability, (ii) no permeability barrier and (iii) no active transport could be calculated using in vitro biomimetic measurements, essentially the Regis Immobilized Artificial Membranes (IAMs) MB/PB Technology® that we are proposing in this paper as a useful tool in early drug discovery [51]
We have shown that IAM MB/PB DEImax showed a better correlation with in vivo log DEImax than Lipophilicity Efficiency (LLE) as it shown in Figure 8a and 8b

Summary

Introduction

Medicinal chemists face multi-factorial challenge problems when designing drug molecules that can reduce the impact or cure a pathological condition; drug discovery scientists seek the smallest possible dose with minimal side effects [1,2,3,4]. We propose that the unbound volume of distribution of compounds is an important parameter to consider, as this in vivo parameter describes the proportion of the dose relative to the free plasma concentration of compounds in steady state [15].

Results

Conclusion