Adrien Albert Award: How to Mine Chemistry Space for New Drugs and Biomedical Therapies

Abstract

It is clear that the sizes of chemical, 'drug-like', and materials spaces are enormous. If scientists working in established therapeutic, and newly established regenerative medicine fields are to discover better molecules or materials, they must find better ways of probing these enormous spaces. There are essentially five ways that this can be achieved: combinatorial and high throughput synthesis and screening approaches; fragment-based methods; de novo molecular design, design of experiments, diversity libraries; supramolecular approaches; evolutionary approaches. These methods either synthesise materials and screen them more quickly, or constrain chemical spaces using biology or other types of 'fitness functions'. High throughput experimental approaches cannot explore more than a minute part of chemical space. We are nevertheless entering into an era that is data dominated. High throughput experiments, robotics, automated crystallographic beam lines, combinatorial and flow synthesis, high content screening, and the 'omics' technologies are providing a flood of data, and efficient methods for extracting meaning from it are essential. This paper describes how new developments in mathematics have provided excellent, robust computational modelling tools for exploring large chemical spaces, for extracting meaning from large datasets, for designing new bioactive agents and materials, and for making truly predictive, quantitative models of the properties of molecules and materials for use in therapeutic and regenerative medicine. We describe these broadly applicable modelling tools and provide examples of their application to serum free stem cell culture, pathogen resistant polymers for implantable devices, new markers and biological mechanisms derived from mathematical analyses of gene array data, and pharmacokinetically important physicochemical properties of small molecules. We also discuss biologically conserved peptide motifs as a design framework for small molecule drugs and give examples of the application of this concept to drug design.

RACI Research Awards 2014

“…Dave Winkler, winner of the Adrien Albert Award for medicinal chemistry, reports on computational chemistry in the design of biologically active compounds and the development of quantitative models for predicting the properties of molecules and materials for use in therapeutic and regenerative medicine. [1] Martin Banwell, winner of the H. G. Smith Medal, reports on intramolecular Alder-ene reactions catalysed by Pd II in the synthesis of carbo-and hetero-cyclic compounds, including the alkaloids hamayne and galanthamine. [2] Jeff Reimers, winner of the Physical Chemistry Award, presents an insightful review highlighting the importance of considering not just the well known concept of reaction coordinates, but also the other motions that accompany those occurring along the reaction coordinate and the effects that each have on spectral and kinetics properties.…”