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Ligand/protein binding (LPB) is a major topic in medicine, chemistry and biology. Since the advent of computers, many scientists have put efforts in developing theoretical models that could decode the alphabet of the LPB interaction. The success of this task passes by the resolution of the molecular mechanism of LPB. In the past century, major attention was dedicated to the thermodynamics of LPB, while more recent studies have revealed that ligand (un)binding kinetics is at least as important as ligand binding thermodynamics in determining the drug in vivo efficacy. In the present review, we introduce the most widely used computational methods to study LPB thermodynamics and kinetics. It is important to say that no method outperforms another, they all have pros and cons and the choice of the user should take carefully into account the system under investigation, the available structural and experimental data, and the goal of the research. A perspective on future directions of method development and research on LPB concludes the discussion. This article is categorized under: Molecular and Statistical Mechanics > Free Energy Methods Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods.

Substitution einer Carboxygruppe: Alle Integrinrezeptoren binden ihre Liganden, die einen Aspartatrest enthalten, in der Metallionen-abhangigen Adhasionsstelle (MIDAS). Bislang waren alle Versuche, die Carboxygruppe durch andere isostere Gruppen mit verbesserten pharmakologischen Eigenschaften zu ersetzen, gescheitert. Nun wurde gezeigt, dass die Carboxygruppe unter Beibehaltung der hohen Bindungsaktivitat durch eine Hydroxamsaureeinheit ersetzt werden kann (Bild: Ligand in der Bindungstasche von αvβ3).

A suitable substitute: All integrin receptors bind their ligands, which contain an aspartate residue, in the metal-ion- dependent adhesion site (MIDAS). So far all attempts to replace the carboxyl group of aspartate with other, pharmacologically favorable isosteric groups have failed. Now it has been shown that a hydroxamic acid group can replace the carboxyl group; the resulting ligand retains its high binding activity. The picture shows one such ligand in the binding site of alphavbeta3.

NMDA receptors are glutamate-gated ion channels (iGluRs) that are involved in several important physiological functions such as neuronal development, synaptic plasticity, learning, and memory. Among iGluRs, NMDA receptors have been perhaps the most actively investigated for their role in chronic neurodegeneration such as Alzheimer's, Parkinson's, and Huntington's diseases. Recent studies have shown that the NTD of subunit NR2B modulates ion channel gating through the binding of allosteric modulators such as the prototypical compound ifenprodil. In the present paper, the construction of a three-dimensional model for the NR2B modulatory domain is described and docking calculations allow, for the first time, definition of the ifenprodil binding pose at an atomic level and fully explain all the available structure-activity relationships. Moreover, in an attempt to add further insight into the ifenprodil mechanism of action, as it is not completely clear if it binds and stabilizes an open or a closed conformation of the NR2B modulatory domain, a matter, which is fundamental for the rational design of NMDA antagonists, MD simulations followed by an MM-PBSA analysis were performed. These calculations reveal that the closed conformation of the R1-R2 domain, rather than the open, constitutes the high affinity binding site for ifenprodil and that a profound stabilization of the closed conformation upon ifenprodil binding occurs. Thus, for a rational design and/or for virtual screening experiments, the closed conformation of the R1-R2 domain should be taken into account and our 3D model can provide valuable hints for the design of NR2B-selective antagonists. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

β-Secretase (BACE-1), a key enzyme in the etiopathogenesis and progression of Alzheimer Disease, is the focus of medicinal chemistry efforts both in the pharmaceutical industry and in academia. Despite the availability of diverse peptidomimetic BACE-1 inhibitors, nonpeptidic compounds suitable for oral delivery and transport across the blood brain barrier are in great demand. Herein, a number of active and structurally diverse inhibitors were selected and subjected to an ensemble-docking process into five BACE-1 X-ray structures. The calculated bioactive conformations of these inhibitors allowed us to build an exhaustive pharmacophore model, which captures both the common geometric and electronic features essential for enzyme inhibition. The model is intended to aid the rational design of new BACE-1 inhibitors. Furthermore, a comparison of BACE/cathepsin D X-ray structures was made to provide guidelines for the design of BACE-selective inhibitors. © 2007 Wiley-VCH Verlag GmbH& Co. KGaA.

Die Bindung der Carboxygruppe eines Aspartatrestes an die Metallionen-abhangige Adhasionsstelle (MIDAS) ist ein Schlusselelement der Ligandenbindung an Integrine. Dies wurde durch die Bindung des cyclischen Pentapeptids cyclo(RGDfNMeV) (Cilengitid) an das Integrin αvβ3 demonstriert (siehe Bild). H. Kessler und Mitarbeiter zeigen in der Zuschrift auf S. 4501 ff., dass sich die Carboxygruppe, die bisher fur unverzichtbar gehalten wurde, durch eine Hydroxamsaureeinheit ersetzen lasst.