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The accurate prediction of protein–ligand binding affinity belongs to one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have become increasingly popular in this respect due to their accuracy and solid theoretical basis. Here, we present a combined study which encompasses experimental and computational studies on two series of factor Xa ligands, which enclose a broad chemical space including large modifications of the central scaffold. Using this integrated approach, we identified several new ligands with different heterocyclic scaffolds different from the previously identified indole-2-carboxamides that show superior or similar affinity. Furthermore, the so far underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for the higher halogen−π aryl interactions. With this challenging example, we demonstrated the ability of the MD-based non-equilibrium free energy calculation approach for guiding crucial modifications in the lead optimization process, such as scaffold replacement and single-site modifications at molecular interaction hot spots.

More than just the sum of its parts: The superadditivity effect of fragment linking on ΔGwas quantified by deconstructing two fXa inhibitors with congeneric fragments, but different linkers. By connecting both fragments with a single bond, a high linker contribution ΔGlinkof −14.0 kJ mol−1results, which corresponds to an improvement in affinity by around 2.5 orders of magnitude relative to the sum of fragment ΔGvalues (see picture).

Mehr als die Summe der Teile: Der Superadditivitätseffekt auf ΔGbeim Verknüpfen von Fragmenten wurde durch das Zerlegen von zwei fXa‐Inhibitoren gleicher Fragmente und verschiedener Linker quantifiziert. Das Verknüpfen zweier Fragmente mit einer einzigen Bindung lieferte einen Linkerbeitrag von −14.0 kJ mol−1, was einer um 2.5 Größenordnungen verbesserten Affinität relativ zur Summe der ΔG‐Werte der Fragmente entspricht (siehe Bild).

Attraktives Chlor: Nichtkovalente Wechselwirkungen zwischen Chlor‐ oder Brom‐Atomen und aromatischen Ringen in Proteinen bieten einen neuen Ansatzpunkt für die Beeinflussung der molekularen Erkennung. Die Einführung dieser Substituenten an spezifischen Positionen zweier Faktor‐Xa‐Inhibitoren erhöht deren freie Bindungsenergie durch die Wechselwirkung mit einer Tyrosineinheit. Das allgemeine Vorkommen dieses Strukturmotivs wird anhand zahlreicher Kristallstukturen und quantenchemischer Rechnungen belegt (siehe Bild).

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The synthesis of non-nucleoside-based phosphoramidites that bear the 2,4-dinitrophenyl group is reported. These labelled phosphoramidites, which have been used in solid-phase oligonucleotide synthesis to attach single and multiple dinitrophenyl groups to the 5′-end of oligonucleotides, are entirely compatible with the normal oligonucleotide synthesis cycle. Multiple labelling can be performed readily in high yield and the resulting oligonucleotides can be purified readily by reversed-phase h.p.l.c. The labelled oligonucleotides have been detected using monoclonal and polyclonal anti-dinitrophenyl antibodies.

This paper reviews family transactional theories of incest and sexual abuse. Two main types of family are described: the chaotic family and the “endogamous” incestuous family. Some general features of incestuous and sexually abusive families are then discussed, after which some basic principles of clinical work with such families are considered.

This paper reviews some of the causes of resistance in families of adolescents being seen in conjoint family therapy. Two main types of resistance are described: resistance due to excessively high anxiety and resistance due to excessively low anxiety. Techniques for dealing with such resistance are then discussed: first, directive techniques designed to lower or heighten anxiety and secondly, strategic techniques designed to exploit resistance to a therapeutic end.

Die Mischung machts: PHONA‐PNA‐Cooligomere wie 1(T=1‐Thymyl) vereinen die hervorragenden Bindungseigenschaften der PNAs mit den verbesserten physikalischen Eigenschaften der PHONAs, insbesondere deren guter Wasserlöslichkeit.

The astonishing discovery that peptide nucleic acids (PNAs, B=nucleobase), in spite of their drastic structural difference to natural DNA, are better nucleic acid mimetics than many other oligonucleotides has resulted in an explosion of research into this class of compounds. The synthesis, physical properties, and biological interactions of PNAs as well as their chimeras with DNA and RNA are summarized here.

Äußerst überraschend war die Erkenntnis, daß Peptidnucleinsäuren (PNAs, B=Nucleobase) trotz ihrer drastisch vom natürlichen DNA-Rückgrat abweichenden Struktur besser als die meisten Oligonucleotidderivate als Nucleinsäuremimetica genutzt werden können. Die Synthese, physikalischen Eigenschaften und biologischen Wechselwirkungen sowohl der PNAs als auch ihrer Chimären mit DNA und RNA werden hier zusammenfassend beschrieben.

A method for amplified reconstruction and noise reduction of a static low-intensity optical field by holography is suggested. The technique consists of a reduction of the reference beam intensity to that of the object field during the holographic exposure. The noise-reduced hologram obtained can then produce the amplified image with an increased reference beam. The technique is demonstrated by the detection of surface scratches on glass.

One objective of psychiatric education can be to help trainees describe and understand major concerns patients experience in their key relationships, inner conflict and sense of self. A precis of major concepts and principles in this area (usually known as psychodynamics) is presented without the metapsychological framework which makes some of the literature difficult to grasp. This is intended to make learning more efficient and to facilitate the formulation of hypotheses about the presence or absence of specific conflicts, and problems in key relationships. We do not propose that these hypotheses necessarily explain psychopathology but that they (a) supplement formal diagnosis; (b) enrich the clinical data base by providing hypotheses which are testable in part by clinical observation and which can be tested scientifically; (c) provide understanding crucial to psychotherapy.

A winning combination!PHONA – PNA co-oligomers such as 1(T = 1-thyminyl) unite the outstanding binding properties of PNAs with the improved physical properties of PHONAs—in particular, their excellent water solubility.

No Abstract

The superadditivityof fragment linking on affinities was quantified by systematic deconstruction of a fXa inhibitor. In their Communication on page 905 ff.,M. Nazaré, H. Matter, and co‐workers show that by connecting two fragments with a single bond, a linker contribution of −14.0 kJ mol−1results, which corresponds to an affinity improvement of about 2.5 orders of magnitude relative to the sum of fragment affinities.

Die Superadditivitätvon Affinitäten beim Verbinden einzelner Fragmente wurde durch systematischen Abbau eines fXa‐Inhibitors quantifiziert. In ihrer Zuschrift auf S. 929 ff.zeigen M. Nazaré, H. Matter et al., dass durch Verbinden einzelner Fragmente mit einer einzigen Bindung ein Linkerbeitrag von −14.0 kJ mol−1erreicht werden kann, was einer Affinitätsverbesserung um ungefähr 2.5 Größenordnungen entspricht (relativ zur Summe der Affinitäten der Fragmente).

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A number of phosphoramldite monomers have been prepared and used in the synthesis of antisense phosphorothioate oligonucleotides bearing 5′-polyalkyl and cholesterol moieties. Similar groups have also been attached to the 3′-end of oligonucleotides by means of functionalised CPG. Melting temperatures of duplexes formed between phosphorothioate oligonucleotides with lipophilic end-groups and complementary DNA strands were found to be identical to those formed by the equivalent unmodified phosphorothioates.

A series of non-nucleoslde-based 2,4-dlnltrophenyl (DNP) phosphoramidltes have been prepared and used in the multiple labelling of ollgonucleotldes during solid-phase synthesis. The length of spacer arm between the DNP label and the ollgonucleotlde phosphate backbone, and the number of attached DNP groups have both been varied In order to determine the optimum conditions for antl-DNP antibody binding. Detection using enzyme-linked colorimetrlc techniques showed sensitivity equivalent to that obtainable using biotinylated oligonucleotides.