Finding Drug Metabolic Sites

Drug Discovery

A software program that could have a significant impact on drug discovery has been developed and tested by a European group.

The program, MetaSite, predicts which part of a potential drug compound will be metabolized by one of the major human cytochrome P450 enzymes. It also predicts which cytochrome will catalyze the process. Cytochrome P450s are key enzymes in the elimination of drugs from the body.

If knowledge of a compound's degradation site could be determined in advance, medicinal chemists could protect that site chemically and thus prolong the compound's lifetime in the body. Chemists could also use the information to prescreen new drug candidates for suitability, design prodrugs (inactive compounds that become drugs when metabolized), or help assess a drug's ADME/Tox (absorption, distribution, metabolism, excretion, and toxicity) properties.

MetaSite was conceived by Ismael Zamora of Lead Molecular Design, Sant Cugat del Valls, Spain, and was codeveloped with chemistry professor Gabriele Cruciani's group at the University of Perugia, Italy, and researchers at Molecular Discovery in London, who now report on its capabilities (J. Med. Chem. 2005, 48, 6970).

Cruciani and coworkers note that earlier computational techniques for predicting metabolic reaction sites are not generally used by pharmaceutical researchers because they're inaccurate, undependable, and difficult to carry out. MetaSite, on the other hand, predicts compound metabolic sites and identifies the cytochrome P450 involved with about 80% accuracy and takes only a few seconds per compound to do so. Required input is a 2-D structure of the compound and 3-D structures of the enzymes, which are already known for the major human cytochrome P450s.

Christopher A. Lipinski, discoverer of the Lipinski rules for predicting compounds' potential as drugs, says: Cruciani and his group have made a valuable contribution to the ADME area by making the MetaSite software available via an Internet download [from www.moldiscovery.com] at no cost for academic and noncommercial use. The group has made using MetaSite as easy as possible for medicinal chemists.

Tudor I. Oprea, chief of the division of biocomputing at the University of New Mexico School of Medicine, calls MetaSite a major breakthrough in our understanding of small molecule-cytochrome P450 interactions. To my knowledge, it's the first in silico method that predicts with at least 70%, but mostly 80% or higher, accuracy the site of metabolism and inhibition of small molecules related to P450 enzymes. True predictivity is achieved, regardless of chemical class.

For preclinical drug discovery, he adds, MetaSite should be on every desktop. It is that important.