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Ligand-protein docking studies of potential HIV-1 drug compounds using the algorithm FlexX
George Patargias, Gary Ewart, Carolyn Luscombe and Wolfgang B. Fischer
Anal Bioanal Chem. 396(7):2559-63, (2010)

The authors in the paper describe how FlexX docking of four compounds to the transmembrane part of the Vpu protein from HIV-1 was undertaken. Due to the common guanidinium group within each of these compounds they can exist in a protonated and unprotonated state. LeadIT was utilized to calculate energy scores to order the molecules within a sequence of predicted affinity, the sequence by suggested FlexX was in accordance with experimental findings based on IC50 values. From two of the derivates with the lowest binding energy, one of them has shown excellent antiviral activity and is currently in clinical trials.
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Identification of the First Low-Molecular-Weight Inhibitors of Matriptase-2
Mihiret Tekeste Sisay, Torsten Steinmetzer, Marit Stirnberg, Eva Maurer, Maya Hammami, Jürgen Bajorath and Michael Gütschow
J.Med.Chem. Publication Date (Web): July 14, 2010

The paper describes how FlexX docking helped researchers from Bonn and Marburg, Germany, in designing the first low-molecular-weight inhibitors of Matriptase-2 – a target of high interest in novel approaches to treat cancer and iron-related maladies. A comparative 3D model of the protein was generated and a virtual screening cascade applied with FlexX used for final ranking of a hit list. Two inhibitors identified have K_i values of 170 and 460 nM for Matriptase-2, whilst a closely related protease matriptase compound with more than 50-fold selectivity over matriptase-2 (K_i = 220 nM), was also identified.
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In Pursuit of Fully Flexible Protein-Ligand Docking: Modeling the Bilateral Mechanism of Binding
Angela M. Henzler and Matthias Rarey
Molecular Informatics, 29:164-173, (2010)

The structure-based design community is confronted with an ever-increasing amount of protein-ligand docking methodologies. A considerable fraction of them states to target not only rigid but also flexible proteins. This review provides an overview of such fully flexible docking algorithms and helps to keep track of current development in the field. The authors established a meaningful classification enabling the readership to compare the approaches, discover strengths and weaknesses, and to assess their applicability to docking scenarios in which protein flexibility is critical.
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