SP ORCalc: A development of a database analysis that provides putative metabolic enzyme reactions for ligand-based drug design

Abstract

Understanding both the enzyme reactions that contribute to intermediate metabolism and the biochemical fate of candidate therapeutic and toxic agents are essential for drug design. Traditional metabolic databases indicate whether reactions have been observed but do not provide the likelihoods of reactions occurring, for example those of mixed function oxygenases and oxidases, during phase I metabolism. The desire for more quantitative predictions motivated the development of the recently introduced Substrate Product Occurrence Ratio Calculator (SP ORCalc) that identifies metabolically labile atom positions in candidate compounds. This paper describes a further development and provides a clearer explanation of SP ORCalc for the computational pharmacology, medicinal chemistry and drug design communities interested in metabolic prediction of xenobiotics using chemical databases of biotransformations. Examples of reaction centre detection in Metabolite™ are described followed by a demonstration of almokalant, an anti-arrhythmic agent, undergoing phase I metabolism. In general, occurrence ratio ( OR) values are calculated throughout a compound and its transformed metabolites to give propensity ( p) values at each atom position. The OR values from substrates and products in the database are essential for addition and elimination reactions. For almokalant, the resulting p values ranged from 10 −1 to 10 −5 and their order of magnitude reflected the known and experimentally observed metabolites. SP ORCalc depends entirely on the level of detail from isoform- or species-specific reaction classes in Metabolite™. Labile atom positions (sites of metabolism) are identified in both the candidate compound and its metabolites. In general, the likelihood of one enzyme isoform-dependent reaction occurring relative to another and the putative metabolic routes from different isoforms can be investigated. SP ORCalc can be developed further to include suitable three-dimensional, structure–activity and physiochemical information.