Biology subjects

Slocum, S.

Publications and source records attributed to Slocum, S..

3 recordsLinked to original sources

bioRxiv2021

Structure-based design of a chemical probe set for the 5-HT5A serotonin receptor

The 5-HT5A receptor (5-HT5AR), for which no selective agonists and only a few antagonists exist, remains the least understood serotonin (5-HT) receptor. A single commercial antagonist (SB-699551) has been widely used to investigate central nervous system (CNS) 5-HT5AR function in neurological disorders, including pain. However, because SB-699551 has affinity for many 5-HTRs, lacks inactive property-matched controls, and has assay interference concerns, it has liabilities as a chemical probe. To better illuminate 5-HT5AR function, we developed a probe set through iterative rounds of molecular docking, pharmacological testing, and optimization. Docking over six million lead-like molecules against a 5-HT5AR homology model identified five mid-M ligand starting points with unique scaffolds. Over multiple rounds of structure-based design and testing, a new quinoline scaffold with high affinity and enhanced selectivity for the 5-HT5AR was developed, leading to UCSF678, a 42 nM arrestin-biased partial agonist at the 5-HT5AR with a much more restricted off-target profile and decreased assay liabilities vs. SB-699551. Site-directed mutagenesis supported the docked pose of UCSF678, which was also consistent with recent published 5-HTR structures. Surprisingly, property-matched analogs of UCSF678 that were either inactive across 5-HTRs or retained affinity for UCSF678s off-targets revealed that 5-HT5AR engagement is nonessential for alleviating pain in a mouse model, contrary to previous studies using less-selective ligands. Relative to SB-699551, these molecules constitute a well-characterized and more selective probe set with which to study the function of the 5-HT5A receptor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/471449v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8fb24dorg.highwire.dtl.DTLVardef@2dd84org.highwire.dtl.DTLVardef@1d3346org.highwire.dtl.DTLVardef@1117331_HPS_FORMAT_FIGEXP M_FIG Table of Contents Graphic C_FIG

biophysics↗

bioRxiv2019

Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys

The chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities, and potential off-target effects of CNO represent areas for improvement. Here we provide a new high affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 g/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 g/kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

neuroscience↗

bioRxiv2019

Designing Peptides on a Quantum Computer

Although a wide variety of quantum computers are currently being developed, actual computational results have been largely restricted to contrived, artificial tasks. Finding ways to apply quantum computers to useful, real-world computational tasks remains an active research area. Here we describe our mapping of the protein design problem to the D-Wave quantum annealer. We present a system whereby Rosetta, a state-of-the-art protein design software suite, interfaces with the D-Wave quantum processing unit to find amino acid side chain identities and conformations to stabilize a fixed protein backbone. Our approach, which we call the QPacker, uses a large side-chain rotamer library and the full Rosetta energy function, and in no way reduces the design task to a simpler format. We demonstrate that quantum annealer-based design can be applied to complex real-world design tasks, producing designed molecules comparable to those produced by widely adopted classical design approaches. We also show through large-scale classical folding simulations that the results produced on the quantum annealer can inform wet-lab experiments. For design tasks that scale exponentially on classical computers, the QPacker achieves nearly constant runtime performance over the range of problem sizes that could be tested. We anticipate better than classical performance scaling as quantum computers mature.

bioengineering↗