Computer-Driven Discovery of GPCR Ligands with New Chemotypes and Functional Selectivity

Explore a presentation from MolSoft's UGM 2023 by Dr. Vsevolod "Seva" Katritch of USC, focusing on computer-driven discovery of GPCR ligands with new chemotypes and functional selectivity. Delve into structure-function relationships and ligand design for GPCRs, core computational technologies, and the design of bitopic ligands for μ-Opioid Receptor. Learn about modulating functional pathways of μ-Opioid receptor by targeting conserved Na* site and discover ongoing and emerging directions in rational structure-based ligand design. Examine major breakthroughs in structure-based virtual ligand screening, including the use of REAL Space for on-demand virtual libraries. Understand proposed acceleration approaches, such as utilizing chemical modularity of REAL libraries and the importance of binding pose in selecting minimal fragments. Gain insights into V-SYNTHES computational benchmarking, analogs-by-catalog optimization, and collaborative applications to diverse targets. Explore Enamine Libraries' evolution from HTS to V-SYNTHES, custom combinatorial libraries based on SuFEx "click" reaction, and the development of novel Angiotensin AT2 antagonists for neuropathic pain, from discovery to (pre)clinical candidate stage.

Intro
Structure-Function and Ligand design for GPCRs
Core Computational Technologies
Design of bitopic ligands for μ-Opioid Receptor
Modulating functional pathways of μ-Opioid receptor by targeting conserved Na* site
Ongoing and Emerging Directions Rational Structure-Based Ligand Design
Outline
How to Discover New Leads for a Protein Target?
Major Breakthroughs for Structure-Based VLS
REAL Space: On Demand Virtual Libraries for Screening
Proposed acceleration approaches
Idea: Use chemical modularity of REAL libraries
Selection of Minimal Fragments: Binding pose matters
V-SYNTHES Computational Benchmarking (with Binding Score & Pose selection)
Analogs-by-Catalog optimization of #523 series
V-SYNTHES 2.1-next level of scale and automation
V-SYNTHES collaborative applications to diverse targets
Enamine Libraries: from HTS to V-SYNTHES
Custom combinatorial libraries based on SuFEx "click" reaction
Novel Angiotensin AT2 antagonists for neuropathic pair From discovery to a (pre)clinical candidate