Structure-based design of allosteric modulators for G protein-coupled receptors using molecular modelling and pharmacology experiments

About the Project

Almost all physiological processes are regulated through the activation of G protein-coupled receptors (GPCRs). It has become widely accepted that most GPCRs possess binding sites spatially distinct from their natural ligand binding site (orthosteric site), termed as allosteric sites. These allosteric sites can be targeted by small molecule ligands to modulate the receptor responsiveness to their natural ligand. Allosteric binding sites offer advantages over orthosteric binding sites in identifying drugs with increased specificity, which translates into a drastic reduction of possible side effects in a therapeutical point of view. However, the discovery of allosteric sites and modulators has been largely serendipitous. A recent breakthrough in structural biology disclosed the 3D structures of several GPCRs and provided opportunities to develop computational technologies for allosteric medicine discovery in GPCRs.

In this project, the student will study a GPCR of interest using molecular dynamics simulations and cheminformatics approaches and predict novel allosteric binders. The predictions will be validated via mutagenesis and cell-based functional assays. The student will learn cutting-edge computational approaches in data collection, mining, and analysis at the interface of chemistry and biology as well as state-of-the art functional assays, facilitating skills development in drug design research applicable in academia and industry.

The student will learn cutting-edge computational approaches in data collection, mining, and analysis at the interface of chemistry and biology as well as state-of-the art functional assays, facilitating skills development in drug design research applicable in academia and industry.

This project strongly aligns with the ‘Life and Health Sciences’ cluster as it will contribute to the design of a novel class of drugs with increased therapeutic efficacy and reduced side effects for a wide range of diseases such as inflammation, infertility, metabolic and neurological disorders, viral infections and cancer.