The rapidly growing wealth of protein and protein-ligand structural information has greatly facilitated rational, structure-based drug discovery. One application of this data has been to enable calculation of alignments and similarity between protein binding sites to assess the risk of off-target effects for a potential ligand, facilitate design of ligands that are selective for targets of interest, and to recognize novel bioisosteres from crystal data. While ligand and sequence-based methods are commonly used to recognize similarities between binding sites, we believe there are unique advantages to including more detailed 3D information of the binding site cavity.  The Rapid Assessment of Binding Site Similarity (RBSS) approach built upon ideas from the IsoMIF method is described.  Interaction fields covering the binding site are computed that indicate the most probable location of ligand features such as hydrophobicity, aromaticity, hydrogen bonding, and charged groups within the binding site cavity.  Alignment of the interaction fields for a pair of binding sites followed by a similarity calculation is performed using our GPU-enabled Shape Screening technology.  This enables comparison of a binding site to all complexes and apo binding sites in the PDB in less than one minute, facilitating rapid hypothesis creation and checking.  The RBSS method shows superior performance in a number of widely used binding site similarity benchmarks.  However, application to off-target effect prediction in drug discovery has revealed fundamental limitations in the use of site-based similarities to predict off-target effects.  We present lessons learned and guidance for the application of RBSS and binding site similarities to drug discovery.<br/>

Rapid binding site similarity determination on a GPGPU: Performance and challenges

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.