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Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Rules from Cross-Company Matched Molecular Pairs Analysis (MMPA).

Kramer, C and Ting, A and Zheng, H and Hert, J and Schindler, T and Stahl, M and Robb, G and Crawford, JJ and Blaney, J and Montague, S and Leach, AG and Dossetter, AG and Griffen, EJ (2017) Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Rules from Cross-Company Matched Molecular Pairs Analysis (MMPA). Journal of Medicinal Chemistry. ISSN 0022-2623

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Abstract

The first large scale analysis of in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) data shared across multiple major pharma has been performed. Using advanced matched molecular pair analysis (MMPA), we combined data from three pharmaceutical companies and generated ADMET rules, avoiding the need to disclose the full chemical structures. On top of the very large exchange of knowledge, all companies involved synergistically gained approximately 20% more rules from the shared transformations. There is good quantitative agreement between the rules based on shared data compared to both individual companies' rules and rules published in the literature. Known correlations between log D, solubility, in vitro clearance, and plasma protein binding also hold in transformation space, but there are also interesting exceptions. Data pools such as this allow focusing on particular functional groups and characterizing their ADMET profile. Finally the role of a corpus of robustly tested medicinal chemistry knowledge in the training of medicinal chemistry is discussed.

Item Type: Article
Uncontrolled Keywords: 0304 Medicinal And Biomolecular Chemistry, 1115 Pharmacology And Pharmaceutical Sciences, 0305 Organic Chemistry
Subjects: Q Science > QD Chemistry
R Medicine > R Medicine (General)
Divisions: Pharmacy & Biomolecular Sciences
Publisher: American Chemical Society
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Date Deposited: 05 Oct 2017 09:39
Last Modified: 05 Oct 2017 09:39
DOI or Identification number: 10.1021/acs.jmedchem.7b00935
URI: http://researchonline.ljmu.ac.uk/id/eprint/7283

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