Advances in the Development of Shape Similarity Methods and Their Application in Drug Discovery

Molecular similarity is a key concept in drug discovery. It is based on the assumption that structurally similar molecules frequently have similar properties. Assessment of similarity between small molecules has been highly effective in the discovery and development of various drugs. Especially, two-dimensional (2D) similarity approaches have been quite popular due to their simplicity, accuracy and efficiency. Recently, the focus has been shifted toward the development of methods involving the representation and comparison of three-dimensional (3D) conformation of small molecules. Among the 3D similarity methods, evaluation of shape similarity is now gaining attention for its application not only in virtual screening but also in molecular target prediction, drug repurposing and scaffold hopping. A wide range of methods have been developed to describe molecular shape and to determine the shape similarity between small molecules. The most widely used methods include atom distance-based methods, surface-based approaches such as spherical harmonics and 3D Zernike descriptors, atom-centered Gaussian overlay based representations. Several of these methods demonstrated excellent virtual screening performance not only retrospectively but also prospectively. In addition to methods assessing the similarity between small molecules, shape similarity approaches have been developed to compare shapes of protein structures and binding pockets. Additionally, shape comparisons between atomic models and 3D density maps allowed the fitting of atomic models into cryo-electron microscopy maps. This review aims to summarize the methodological advances in shape similarity assessment highlighting advantages, disadvantages and their application in drug discovery

Identification of Sumoylation Inhibitors Targeting a Predicted Pocket in Ubc9

Sumoylation is a post-translational modification that plays an important role in a wide range of cellular processes. Among the proteins involved in the sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for sumoylation and plays a central role by interacting with almost all of the partners required for sumoylation. Ubc9 has been implicated in a variety of human malignancies. In order to exploit the therapeutic potential of Ubc9, we have identified the potential site to target for rational drug design using molecular modeling approaches. The structural information derived was then used to prioritize hits from a small-molecule library for biological assay using a virtual screening protocol that involves shape matching with a known inhibitor inhibitors and docking of a small-molecule library utilizing computational approaches that incorporate both ligand and protein flexibility. Nineteen compounds were acquired from different chemical vendors and were tested for Ubc9 inhibitory activity. Five compounds showed inhibitory activity against Ubc9, out of which one compound was selected for further optimization. A similarity search was then carried out to retrieve commercially available derivatives, which were further acquired and assayed, resulting in two compounds with acceptable potency. These two compounds can be used as starting points for the development of more potent inhibitors of Ubc9 targeting the predicted site