Jigsaw puzzles at atomic resolution: Computational design of GPCR drugs from fragments

Informazioni relative al progetto

FRAGMENT2DRUG

ID dell’accordo di sovvenzione: 715052

DOI

10.3030/715052

Progetto chiuso

Data della firma CE 15 Maggio 2017

Data di avvio 1 Novembre 2017

Data di completamento 30 Aprile 2023

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 1 467 500,00

Contributo UE

€ 1 467 500,00

Coordinato da

UPPSALA UNIVERSITET
Sweden

Periodic Reporting for period 4 - FRAGMENT2DRUG (Jigsaw puzzles at atomic resolution: Computational design of GPCR drugs from fragments)

Periodo di rendicontazione: 2022-05-01 al 2023-04-30

Sintesi del contesto e degli obiettivi generali del progetto

The objective of this project was to develop a computational platform to accelerate the early drug discovery process for G protein-coupled receptors (GPCRs), which are a class of important therapeutic targets. Computational modeling based on atomic-level models of GPCRs, combined with extensive experimental testing, enabled discovery of GPCR ligands. The conclusion of the action is that fragment-based lead discovery and structure-based modeling can be a powerful strategy to identify starting points for development of novel drugs. The results of the project are important for society as they can lead to novel therapeutic drugs of neurodegenerative diseases and accelerate the drug discovery process, which could improve human health.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

A combination of different computational techniques was first used to improve understanding of how to GPCRs bind ligands and to develop computational fragment-based strategies for efficient drug design. We then applied the developed techniques to identify ligands of therapeutically relevant GPCRs and enzymes using fragment-based lead discovery. In the applied projects, we explored strategies to design drugs that modulate several targets (polypharmacology) and successfully identified novel starting points for development of drugs for treatment of Parkinson’s disease. We also accomplished our goal to discover ligands of peptide-binding GPCRs using a fragment-based approach and identified ligands of Neurotensin receptors. The results of the action have been disseminated in 13 scientific publications and via presentations at conferences.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

This project progressed beyond the state of the art by developing techniques that enable very efficient fragment-based discovery of GPCR ligands by performing structure-based virtual screening of large chemical libraries. In the applied part of the project, the rational design of polypharmacology is the most significant achievement. A common property of drugs (e.g. antipsychotics) is that such compounds interact with multiple targets, which is essential for their therapeutic effect. However, the fact that multi-target interactions may be required for treatment of complex diseases contrasts with the philosophy of modern drug discovery, which focuses on ligands with selectivity for a one target. Although potential of polypharmacology is clear, progress has been limited by difficulties to rationally design such compounds. We undertook the challenge to design ligand polypharmacology relevant for Parkinson’s disease. The project successfully used structure-based modelling to design a single compound with the ability to modulate the activity of two GPCRs. The most potent dual-target compounds display high potency at both targets and one scaffold was demonstrated to be active in a rat model of parkinsonism.

Summary of project