Computational medicinal chemists Albert Kooistra and Chris de Graaf set a new world record virtual screening for the identification of novel pharmaceutical drugs.

Researchers from the Division Medicinal Chemistry have used computersimulations to discover novel ligands for the histamine H1 receptor (H1R), a key player in inflammation.Albert Kooistra MSc and his supervisor Dr. Chris de Graaf(from the Computer-Aided Molecular Design team in the Medicinal Chemistry group led by Dr. Iwan de Esch and Prof. Dr. Rob Leurs) developed a newin silicomethod to select a small set of molecules from a large chemical library of millions of compounds.They predicted that molecules that could adopt similar binding posesin their simulations as the experimentally determined binding mode of the inhibitor doxepin in the recently solved histamine H1R crystal structure, would also have affinity for the H1 receptor.

With this approach Kooistra and De Graaf established a new world record in virtual screening: 73% of the computationally predicted hits were indeed experimentally confirmed as inhibitors of the H1 histamine receptor. The validated in silico hits were furthermore chemically novel (not similar to previously known H1R ligands) and relatively small, making them attractive starting point for so-called Fragment-Based Drug Design (FBDD). This is anew approach in drug discovery that has not yet been applied to H1R orotherG Protein-Coupled Receptors (GPCRs), the largest class of transmembrane proteins that mediatecell signaling.The customized computer-aided screening approach used in the study of Kooistra and De Graaf opens up novel opportunities for designing novel ligands for the pharmaceutically important GPCR family.

De Graaf, C., Kooistra, A.J., Vischer, H.F., Katritch, V., Kuijer, M., Shiroishi, M., Shimamura, T.,  Iwata, S., Stevens, R.C.,, de Esch, I.J.P., Leurs, R. Crystal structure-based virtual screening for novel fragment-like ligands of the human histamine H1 receptor. J Med Chem. 54: 8195-206.

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