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In silico hit hunters: virtual reality in drug discovery

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

picture: Computational medicinal chemists Albert Kooistra (ls) and Chris de Graaf (right) have set a new world record virtual screening by the computer-aided selection of a diverse set of novel fragment-like inhibitors of the histamine H₁ receptor (a key player in inflammation) from a large chemical library with a remarkably high success rate of 73%.

Researchers from the AIMMS section of medicinal chemistry have used computer simulations 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 new in silico method 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 poses in 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 a new approach in drug discovery that has not yet been applied to H₁R or other G Protein-Coupled Receptors (GPCRs), the largest class of transmembrane proteins that mediate cell 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.