Proteochemometric modeling as a tool to design selective compounds and for extrapolating to novel targets

Abstract

‘Proteochemometric modeling’ is a bioactivity modeling technique founded on the description of both small molecules (the ligands), and proteins (the targets). By combining those two elements of a ligand – target interaction proteochemometrics techniques model the interaction complex or the full ligand – target interaction space, and they are able to quantify the similarity between both ligands and targets simultaneously. Consequently, proteochemometric models or complex based models, can be considered an extension of QSAR models, which are ligand based. As proteochemometric models are able to incorporate target information they outperform conventional QSAR models when extrapolating from the activities of known ligands on known targets to novel targets. Vice versa, proteochemometrics can be used to virtually screen for selective compounds that are solely active on a single member of a subfamily of targets, as well as to select compounds with a desired bioactivity profile – a topic particularly relevant with concepts such as ‘ligand polypharmacology’ in mind. Here we illustrate the concept of proteochemometrics and provide a review of relevant methodological publications in the field. We give an overview of the target families proteochemometrics modeling has previously been applied to, and introduce some novel application areas of the modeling technique. We conclude that proteochemometrics is a promising technique in preclinical drug research that allows merging data sets that were previously considered separately, with the potential to extrapolate more reliably both in ligand as well as target space.