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Fragmental modeling of human glutamate transporter EAAT1 and analysis of its binding modes by docking and pharmacophore mapping.
Alessandro Pedretti, Laura De Luca, Cristina Sciarrillo, and Giulio Vistoli
ChemMedChem 3(1):79-90. (2008)

The authors validate a model for EAAT1, the human Glutamate Transporter, which is important in regulating the amount of extracellular L-glutamate. This amino acid represents the main excitatory neurotransmitter in the mammalian CNS.
Using FlexX as a docking tool, the authors obtained relevant correlation between docking scores and bioactivity of EAAT1 blockers. The obtained results let them discriminate between different substrates, and they could identify an apolar region in a set of blockers for a suitable hydrophobic pocket.
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Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121)
Jean-François Bonfanti, Christophe Meyer, Frédéric Doublet, Jérôme Fortin, Philippe Muller, Laurence Queguiner, Tom Gevers, Peggy Janssens, Heidi Szel, Rudy Willebrords, Philip Timmerman, Koen Wuyts, Pieter van Remoortere, Frans Janssens, Piet Wigerinck, and Koen Andries
J. Med. Chem. 51(4):875-96. (2008)

The authors describe a study in which they used FlexX docking to indentify improved binders against Respiratory Syncytical Virus (RSV). They recovered initial nanomolar activity for inhibitors, despite the fact that the binding pocket features a hydrophobic groove and one key interaction takes place at the surface of a coil, which makes docking challenging. In addition and proving their method, one docked structure shows very convincing similarites with an X-ray structure of the core domain of the protein.
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Receptor-based modeling and 3D-QSAR for a quantitative production of the butyrylcholinesterase inhibitors based on genetic algorithm.
Zaheer-ul-Haq, Reaz Uddin, Hongbin Yuan, Pavel A. Petukhov, M. Iqbal Choudhary, and Jeffry D. Madura
J. Chem. Inf. Model. 48(5):1092-103. (2008)

The authors created 3D-QSAR models using CoMFA and CoMSIA for a series of structurally related steroidal alkaloids as butyrylcholinesterase (BuChE) inhibitors. FlexX was used to position the inhibitors into the BuChE active site to determine the most likely binding mode. Multiple inhibitor conformations were used in an attempt to obtain a more reliable 3D-QSAR model. These multiple conformations were derived using the FlexS program. A genetic algorithm based CoMFA approach was found to perform better than CoMSIA. The results demonstrate that the combination of ligand-based and receptor-based modeling with use of a genetic algorithm is a powerful approach to build 3D-QSAR models.
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A virtual screen for diverse ligands: discovery of selective G protein-coupled receptor antagonists.
Stanislav Engel, Amanda P. Skoumbourdis, John Childress, Susanne Neumann, Jeffrey R. Deschamps, Craig J. Thomas, Anny-Odile Colson, Stefano Costanzi, and Marvin C. Gershengorn
J. Am. Chem. Soc. 130(15):5115-23. (2008)

GPCR virtual screening is problematic due to the scarcity of detailed structural information and the intrinsic function-associated structural flexibility of GPCRs. Here a virtual screen of 1 million compounds with FlexE against a homology model was performed to select a diverse subgroup of 100 compounds. This permitted to authors to experimentally identify five structurally diverse antagonists for the thyrotropin-releasing hormone receptors (TRH-R1 and TRHR2).
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