PhD conferral Shanliang Sun
In Silico Medicinal Chemistry: Focus on GPCRs as Privileged Family of Drug Targets
Prof.dr. R. Leurs & Prof.dr. I.J.P. de Esch, copromotor Dr. C. de Graaf
Amsterdam Institute of Molecular and Life Sciences
G protein-coupled receptors (GPCRs) belong to one of the largest gene families. The proteins span the cell membrane and efficiently convert the binding of extracellular chemical messengers (ligands) into distinct intracellular signaling cascades that have a pronounced effect on cell chemistry. Considering the prominent role of GPCRs in (patho)physiology, it is not surprising that over 30% of the currently marketing small-molecule drugs are targeting these receptors.
In this thesis, computational techniques, including data mining, homology modeling, structural analysis to retrieve interaction fingerprints (IFPs), chemoinformatics, chemogenomics, structure-based virtual screening, pharmacophore queries and other computer-aided drug design tools are used to reach the following objectives:
1. To understand and predict GPCR-ligand interactions by combining bioactivity data, mutagenesis data, ligand and protein structures.
2. To investigate structure-based virtual screening protocols for discovering novel ligands using GPCR crystal structures.
3. To identify the molecular determinants for guiding ligand optimizations and prediction of selective GPCR ligands.
The work described in this thesis illustrates the power of data mining, data management and data processing in drug discovery and has resulted in comprehensive annotated databases that are useful in medicinal chemistry projects that focus on individual targets. The databases will also be useful in machine learning and AI applications that aim to develop new and potent ligands with a well-defined poly-pharmacological profile, leading to new opportunities in drug discovery.