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Ligand Selectivity for the Acetylcholine Binding Site of the Rat α5β2 and α3β4 Nicotinic Sub-types Investigated by Molecular Docking
Bisson, W. H.; Scapozza, L.; Westera, G.; Mu, L.; Schubiger, P. A

In this carefully conducted study, the authors analyze and correlate docking results with the selectivity of ligands. Their experimental protocol comprises a thorough optimization of crystal input data. The ten best FlexX docking poses were analyzed in the framework of a consensus scoring scheme. New insights on the binding modes and their characteristics could successfully be derived.

In silico fragment-based discovery of DPP-IV S1 pocket binders
Rummey, C.; Nordhoff, S.; Thiemann, M.; Metz, G.

The authors present an approach to designing Dipeptidyl Peptidase IV inhibitors by virtual screening. Specifically low molecular weight 'needles' for the S1-pocket of this protein were sought for using docking. As such binding fragments usually exhibit low affinity in the mycromolar range, this is not a trivial task. Therefore, additional insight about binding modes from crystallographic data was taken into account.
FlexX-Pharm was able to successfully place the 'needles' close to observed positions of similar fragments in larger inhibitors. However, the scoring function was not able to dicriminate low-affinity binders from the remaining molecules. Still, based on this approach, several diverse low molecular weight inhibitors exhibiting activities in the micromolar range could be identified as starting points for structure-based design.

Structure-Based Design, Synthesis, and Biological Evaluation of Novel Inhibitors of Human Cyclophilin A
Guichou, J.-F.; Viaud, J.; Mettling, C.; Subra, G; Lin, Y.-L.; Chavanieu, A.

With FlexX, French Scientists Find Novel Potent Inhibitors of Human Cyclophilin A that are Lead Candidates for HIV Treatment, too.
Investigators around Alain Chavanieu at the highly renowned CBS and CNRS institutes in Montpellier, France, have successfully used FlexX to go through a textbook-like workflow to find novel Cyclophilin A (CypA) inhibitors. The group started out with the public crystal structure and identified important active site residues by site-directed mutagenesis. A subsequently derived pharmacophore was employed in a 3D search of the available chemicals directory (ACD). The resulting 3129 compounds passed the next step of FlexX screening and co-evaluation with X-score. An outcome of 31 purchased compounds exhibited 9 active members, five of which inhibited more than 80% of the isomerase activity of CypA. Further FlexX-assisted compound optimization resulted in nanomolar inhibition. It turned out in fact that some of these compounds also showed potency to inhibit the HIV-1 replication cycle.