There are many different biological processes in all organisms that distinguish molecules based on their shape. The concept is a fundamental consideration in rational drug design. Relying on just the shape of molecules to find or design compounds with a desired potency has a background in bioisosterism; molecules that are similar in size and shape are more likely to show similar activity towards the same target macromolecule. The pharmaceutical industry uses this concept to improve potential drugs that have good activity but have other properties that are suboptimal.<br/>More and more approaches are used to describe molecular shape. Among them there are the shape fingerprint and shape multipole methods. Shape fingerprints are binary bit strings that encode the shape of compounds. The shape is measured indirectly by alignment to a database of standard shapes. The shape multipoles method describes the distribution of a molecule’s volume using centroids and multipoles (monopole, dipoles, quadrupole, octupole moments).  An interpretation of these multipoles will be presented.<br/>A test set described by Taylor et al. was used to evaluate the performance of both methods. The test set consists of 10 groups of protein-ligand complexes from the PDB that have been selected to be of good quality and therefore define the bioactive conformation. We have generated shape fingerprints for every compound in the test set and calculated shape quadrupoles and octupoles). Molecules were compared with each other based on their shape fingerprints as well as based on the calculated multipoles. The performance of both methods was evaluated using logistic regression and AUC values.<br/>Shape fingerprints use many bits (typically hundreds) to describe shapes whereas shape multipoles reduce the description to fourteen values.  As might be expected, this causes the fingerprints to be prone to over-fitting whereas the multipoles are often not able to describe the shape in enough detail.

Shape described by numbers – Comparing the shape fingerprint and shape multipole methods

253rd National Meeting (2017)

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