This perspective provides a detailed description of the ways in which molecular shape is modelled and utilised to enhance drug discovery. The authors address how molecular shape modelling has impacted three questions essential in medicinal chemistry: “What is the essence of a molecule? What is it made of? What will it do?” Starting with virtual screening, the perspective details how programs like ROCS (rapid overlay of chemical structures) and SQW (SemiQuantitative reWrite) can be used to find new ligands for targets given a known ligand. These programs use atom-centred Guassians, coloured by atom type, to represent molecules as functionalised volumes that can be overlayed and compared. The authors also highlight the importance of molecular shape in lead optimisation; specifically for the identification of bioisosteres for the improvement of pharmacokinetic properties while maintaining or improving target potency. Furthermore, an extensive review of the use of molecular shape modelling in protein crystallography and ligand pose prediction is given, highlighting technologies and examples where both the molecular shape and torsional strain are optimised to provide realistic ligand poses. Molecular shape is also shown to be a useful metric in the design of diverse compound libraries with algorithms developed to design the molecular shape space of interest and cluster compounds into diverse shape clusters. The authors also describe examples of how Guassian-based molecular shape representations can aid in the design of protein-protein inhibitors, which are notoriously hard to design due to the flat nature of the protein interaction surfaces. Next, an alternative method for molecular shape description is introduced that describes the shape as a surface by placing the molecule in a grid of points in space and recording the minimal distances of the points to the molecular surface; a method that has been utilised for 3D QSAR modelling. Finally, the authors present a comparison of several approximate shape methods that provide quick results for pre-filtering large datasets before more exhaustive calculations can be performed.
In summary, understanding molecular shape can make an impact in many areas of drug discovery and a variety of Guassian or surface -based modelling programs have been developed to aid the medicinal chemist. This review offers an extensive description of such approaches and their example uses, and is a great read for those wishing to develop their understanding of the field.
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