Learning and Prediction of Complex Molecular Structure-Property Relationships

The problem of modeling and predicting complex structure-property relationships, such as the absorption, distribution, metabolism, and excretion of putative drug molecules is a fundamental one in contemporary drug discovery. An accurate model can not only be used to predict the behavior of a molecule and understand how structural variations may influence molecular property, but also to identify regions of molecular space that hold promise in context of a specific investigation. However, a variety of factors contribute to the difficulty of constructing robust structure activity models for such complex properties. These include conceptual issues related to how well the true bio-chemical property is accounted for by formulation of the specific learning strategy, algorithmic issues associated with determining the proper molecular descriptors, access to small quantities of data, possibly on tens of molecules only, due to the high cost and complexity of the experimental process, and the complex nature of bio-chemical phenomena underlying the data. This chapter attempts to address this problem from the rudiments: the authors first identify and discuss the salient computational issues that span (and complicate) structure-property modeling formulations and present a brief review of the state-of-the-art. The authors then consider a specific problem: that of modeling intestinal drug absorption, where many of the aforementioned factors play a role. In addressing them, their solution uses a novel characterization of molecular space based on the notion of surface-based molecular similarity. This is followed by identifying a statistically relevant set of molecular descriptors, which along with an appropriate machine learning technique, is used to build the structure-property model. The authors propose simultaneous use of both ratio and ordinal error-measures for model construction and validation. The applicability of the approach is demonstrated in a real world case study.