Brian K. Shoichet

Large scale prospective evaluation of co-folding across hundreds of Mac1-ligand complexes and three virtual screens

On 489 evaluable new Mac1 complexes, AlphaFold3, Chai-1 and Boltz-2 placed over half of ligands within 2 Å, but on docking hit-lists AF3 and Boltz-2 added little over docking.

Structure based discovery of antipsychotic-like TAAR1 agonists

The paper identifies TAAR1 agonists with antipsychotic-like effects through computational screening and experimental validation, showing improved potency and reduced side effects in a schizophrenia model.

Library docking for Cannabinoid-2 Receptor ligands

This study uses library docking to identify subtype-selective CB2 receptor ligands, finding improved hit rates and affinities with larger libraries and structure-based optimization.

Toward a Random Background for Ligand Optimization

This study systematically evaluates the effectiveness of random small perturbations in ligand optimization, finding 11.2% of analogs improved potency by ≥10-fold but often had worse pharmacokinetics.

The selectivity implications of docking libraries with greater and lesser similarities to bio-like molecules

The paper tests if molecules from ultra-large libraries are more selective than those from bio-like libraries, finding similar off-target activity despite differences in chemical novelty.

Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo

This paper identifies AVI-6451, an orally bioavailable inhibitor of SARS-CoV-2 Mac1 with once-daily efficacy in a mouse model.

Drug-induced phospholipidosis as an artifact in antiviral drug repurposing

The paper identifies phospholipidosis as a common artifact in antiviral drug repurposing and introduces a microplate-based assay to detect it, finding that 65% of tested drugs induce it.

The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

This study identifies Mac1 as a therapeutic target for SARS-CoV-2 and demonstrates that AVI-4206, a small molecule inhibitor, reduces viral replication and improves survival in an animal model.

A Cooperative Model for Symmetric Ligand Binding to Protein Fibrils

The paper develops a cooperative binding model for ligands to protein fibrils, relating measured EC50 and IC50 values to intrinsic affinity and cooperativity.

Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning

Shape-based fragment merging (FrankenROCS) with Thompson sampling over 22 billion molecules found neutral SARS-CoV-2 macrodomain inhibitors; analogs reached single-digit micromolar IC50, backed by 137 crystal structures.

A database for large-scale docking and experimental results

The paper develops a database of docking results and experimental data to improve benchmarking and chemical space exploration.

Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus-MPro inhibitors with potent in vivo efficacy

This paper describes the discovery of new coronavirus MPro inhibitors with improved pharmacokinetics, broad-spectrum antiviral activity, and superior in vivo efficacy compared to existing drugs.

Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects

The paper screens 14.6 million virtual isoquinuclidines against opioid receptors to identify dual antagonists-inverse agonists with reduced withdrawal effects compared to naloxone.

The impact of Library Size and Scale of Testing on Virtual Screening

This paper tests the impact of library size and testing scale on virtual screening by comparing results from 1.7 billion vs. 99 million molecule libraries against AmpC β-lactamase, finding improved hit rates and potency with larger libraries.

Cryo-EM structure of Alzheimer disease tau filaments with PET ligand MK-6240

The paper determines the cryo-EM structure of Alzheimer's disease tau filaments bound by the PET ligand MK-6240, revealing key binding interactions that inform ligand design.

Identifying Artifacts from Large Library Docking

The paper identifies docking artifacts in large library screens by rescoring top-ranked molecules with orthogonal methods, finding that 39 predicted cheaters failed experimental testing while 57% of plausible actives showed inhibition.

Profiling the proximal proteome of the mu opioid receptor identifies novel regulators of receptor signaling and trafficking

The paper identifies novel regulators of mu opioid receptor signaling and trafficking using proximity labeling and proteomics.

Ligand Strain Energy in Large Library Docking

This paper introduces a method to calculate ligand strain energy using torsional populations from the Cambridge Structural Database, improving docking hit rates by filtering strained decoys.