The long-term goal is to develop ligand discovery methods, applying these to questions of active biological interest. We have four foci: i. development of new computational docking methods, testing these in simple experimental model systems (supported by GM59957). ii. Application of these methods to G Protein Coupled Receptors (GPCRs), which are intensely studied for the biology they confer, and wonderful templates for large- scale docking (U19 GM106990). iii. Investigation of the mechanism and impact of colloidal aggregation in drug discovery. These small molecule colloids, are the greatest source of artifacts in early discovery, and affect molecules throughout the drug development pipeline (GM71630). iv. Whereas our first three foci adopt a target-based view of ligand discovery, our fourth area returns to classical pharmacology, adopting a ligand- based chemoinformatic strategy that seeks not to discover new ligands for established targets, but rather for established drugs and reagents attempts to predict targets. This project has been the venue for the public access tools for chemoinformatics, databases, and docking (GM71896). Here we extend these projects. i. New docking methods are developed, including treating ordered waters, covalent recognition, and ligand internal energy strain. These are tested experimentally?by calorimetry and crystallography?in the model cavity sites. ii. Working with the Kobilka and Roth labs, we seek novel chemotypes for GPCRs including the - opioid receptor, the muscarinic M2 and M3 receptors, and the ?2-adrenergic receptors; a particular focus are allosteric ligands. iii. We deepen our investigation of the physical mechanism and impact colloidal aggregates, focusing on their persistence among late stage clinical candidates, their structure and mechanism, and antibody conjugates that specifically deliver colloidal drug payloads to cells. iv. Tool and database development remains a key focus. A new direction for the chemoinformatics is a comprehensive and systematic comparison of targets organized by sequence or by bioinformatics similarity, to the same targets organized by the similarity of their ligands. Preliminary results suggest target pairs organized by sequence, co- expression or protein-protein interactions are orthogonal to pairs related by similar ligands. A physical basis is explored.
This proposal seeks develops new methods for drug discovery, applying these to questions of urgent biological interest. A practical outcome are tools useful to chemical biologists and drug discovery scientists, and particular molecules that can illuminate new aspects of cell signaling. A small number of these molecules may be leads towards new drugs.
| Wang, Sheng; Che, Tao; Levit, Anat et al. (2018) Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature 555:269-273 |
| McCorvy, John D; Butler, Kyle V; Kelly, Brendan et al. (2018) Structure-inspired design of ?-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol 14:126-134 |
| Korczynska, Magdalena; Clark, Mary J; Valant, Celine et al. (2018) Structure-based discovery of selective positive allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor. Proc Natl Acad Sci U S A 115:E2419-E2428 |
| Liu, Hongtao; Hofmann, Josefa; Fish, Inbar et al. (2018) Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists. Proc Natl Acad Sci U S A 115:12046-12050 |
| Weiss, Dahlia R; Karpiak, Joel; Huang, Xi-Ping et al. (2018) Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets. J Med Chem 61:6830-6845 |
| Balius, Trent E; Fischer, Marcus; Stein, Reed M et al. (2017) Testing inhomogeneous solvation theory in structure-based ligand discovery. Proc Natl Acad Sci U S A 114:E6839-E6846 |
| Maciejewski, Mateusz; Lounkine, Eugen; Whitebread, Steven et al. (2017) Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets. Elife 6: |
| Ganesh, Ahil N; Logie, Jennifer; McLaughlin, Christopher K et al. (2017) Leveraging Colloidal Aggregation for Drug-Rich Nanoparticle Formulations. Mol Pharm 14:1852-1860 |
| Fish, Inbar; Stößel, Anne; Eitel, Katrin et al. (2017) Structure-Based Design and Discovery of New M2 Receptor Agonists. J Med Chem 60:9239-9250 |
| Roth, Bryan L; Irwin, John J; Shoichet, Brian K (2017) Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol 13:1143-1151 |
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