Clinical and Experimental Pharmacology and Physiology (2003) 30, 836–840 Annual Scientific Meeting of ASCEPT 2002 IN SILICO INSIGHTS: CHEMICAL AND STRUCTURAL CHARACTERISTICS ASSOCIATED WITH URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASE SUBSTRATE SELECTIVITY PA Smith,* MJ Sorich, † RA McKinnon † and JO Miners* *Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre and † School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, Adelaide, South Australia, Australia SUMMARY 1. Undesirable absorption, distribution, metabolism, excre- tion properties are the cause of many drug development failures and this has led to the need to identify such problems earlier in the development process. This work highlights computational (in silico) approaches used to identify charac- teristics influencing the metabolism of uridine diphosphate (UDP)-glucuronosyltransferase (UGT) substrates. Uridine diphosphate-glucuronosyltransferase facilitates conjugation between glucuronic acid and a nucleophilic site within a substrate and is one of the major drug-metabolizing enzymes. 2. An understanding of the relevant structural and chemical characteristics of the ligand and the enzyme active site will lead to greater utilization of metabolically relevant structural information in drug design. However, an X-ray crystal structure of UGT is not yet available, little has been reported about important structurally or catalytically relevant amino acids and only recently has the reported substrate profile of UGT isoforms reached an interpretable level. 3. A database of all the known substrates and non- substrates for each human UGT isoform was assembled and a range of modelling approaches assessed. Currently, pharma- cophore models developed using Catalyst™ (Accelrys, San Diego, CA, USA) indicate that substrates of the UGT1A family share two key hydrophobic regions 3 and 6–7 Å from the site of glucuronidation in a well-defined spatial geometry. Further- more, two-dimensional quantitative structure-activity relation- ship models show significant reliance on substrate lipophilicity and a range of other descriptors that are known to capture information relevant to ligand–protein interactions. 4. In conclusion, substrate-based modelling of UGT appears both useful and feasible, with significant potential for deter- mining aspects of chemical structure associated with metabo- lism and to quantify the nature of the relationship for UGT substrates. The development of a novel, user-defined ‘glucuro- nidation feature’ for alignment was crucial to the development of pharmacophore-based UGT models. Key words: absorption, distribution, metabolism, excretion (ADME), metabolism, molecular modelling, pharmacophore, quantitative structure–activity relationship (QSAR), uridine diphosphate-glucuronosyltransferase (UGT). INTRODUCTION Modern drug development is an expensive and time-consuming process. Many drug candidates proceed to development only to fail in clinical trials. Unfavourable absorption, distribution, metabo- lism, excretion (ADME) properties of new drug candidates cause many of these failures and this has generated intense efforts to identify potential ADME challenges early in the drug discovery process. 1 In this regard, computational (in silico) and in vitro ADME approaches are now widely used throughout the discovery process to optimize selection of the most suitable drug candidates for development. 2 Many drug leads are found to be unsuitable for clinical use at later stages of development due to problems with metabolism. 1 Elimination by an enzyme exhibiting genetic polymorphism and involvement in undesirable drug–drug interactions may cause rejection of a compound as a useful therapeutic agent. As a result, an integral component of modern ADME evaluation is the identifi- cation of the enzyme(s) responsible for the metabolism of a new chemical entity, together with an estimate of kinetic parameters. Glucuronidation, catalysed by the microsomal enzyme uridine diphosphate (UDP)-glucuronosyltransferase (UGT), is an essential clearance mechanism for drugs from all therapeutic classes. 3 Uridine diphosphate-glucuronosyltransferase catalyses conju- gation of glucuronic acid to OH, NH and SH groups of small organic chemicals, thus increasing water solubility and the ease of removal from the body. Consistent with its broad substrate profiles, the UGT consists of a superfamily of independently regulated Correspondence: Dr Paul Smith, Department of Clinical Pharmacology, Flinders University, PO Box 2100, Adelaide, SA 5000, Australia. Email: Paul.Smith@flinders.edu.au Presented at the 36th Annual Scientific Meeting of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, Melbourne, 25–29 November 2002. Received 11 February 2003; revision 16 April 2003; accepted 27 April 2003.