Towards holistic Compound Quality Scores: Extending ligand efficiency indices with compound pharmacokinetic characteristics.

The suitability of small molecules as oral drugs is often assessed by simple physicochemical rules, the application of ligand efficiency scores or by composite scores based on physicochemical compound properties. These rules and scores are empirical and typically lack mechanistic background, such as information on pharmacokinetics (PK). We introduce new types of Compound Quality Scores (CQS, specifically called dose scores and cmax scores), which explicitly include predicted or, when available, experimental PK parameters and combine these with on-target potency. These CQS scores are surrogates for an estimated dose and corresponding cmax and allow prioritizing of compounds within test cascades as well as before synthesis. We demonstrate the complementarity and, in most cases, superior performance relative to existing efficiency metrics by project examples.

Negation and Negative Concord in Georgian Sign Language.

Negation is a topic that has received considerable attention ever since the early days of sign language linguistics; also, it is one of the grammatical domains that has given the impetus for sign language typology. In this paper, we offer a typological and theoretical contribution to the study of sign language negation. As for the typological side, we add Georgian Sign Language (GESL) to the pool of languages investigated. Our description reveals that GESL displays a number of typologically unusual features: a considerable number of negative particles, including emphatic, prohibitive, and tense-specific particles; specialized negative modals; and a wide range of possibilities for Negative Concord (NC) involving two manual negative signs, including a unique tense-specific instance of NC. Most of the patterns we report-available negative particles, their clausal position, and NC possibilities-are clearly different from those attested in spoken Georgian. As for the theoretical contribution, we investigate how the highly complex GESL negation system compares to existing taxonomies of NC and Double Negation systems, and we conclude that GESL aligns with certain languages that have been classified as atypical NC languages.

Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design.

OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist. Moderately selective OX1 antagonists comprising a [2.2.1]-bicyclic scaffold served as our starting point. Based on our binding mode hypothesis, we postulated which part of the scaffold points toward one of the regions where the two binding pockets differ. Structural changes in this part resulted in a modified core with higher inherent selectivity compared to the [2.2.1]-bicyclic template. The structure-based design, synthesis, and hit-to-lead evaluation of this novel OX1 receptor-selective scaffold are discussed herein.

Structure and Grammaticalization of Serial Verb Constructions in Sign Language of the Netherlands-A Corpus-Based Study.

In serial verb constructions (SVCs), multiple independent lexical verbs are combined in a mono-clausal construction. SVCs express a range of grammatical meanings and are attested in numerous spoken languages all around the world. Yet, to date only few studies have investigated the existence and functions of SVCs in sign languages. For the most part, these studies-including a previous study on Sign Language of the Netherlands (NGT)-relied on elicited data. In this article, we offer a cross-modal typological contribution to the study of SVCs by investigating the phenomenon based on naturalistic corpus data from NGT. A search of the Corpus NGT yielded 41 mono-clausal utterances in which one of a closed set of verbs-namely go, give, take, and call-combines with another lexical verb. While the combinations we found are in important respects reminiscent of SVCs described for spoken languages, our data also confirm the previous finding that the fixed verb in the SVC serves to express agreement (by means of spatial modulation) when the other verb cannot do so. In addition, we identified some novel uses of the verbs go and give: (i) go functioning as a future tense marker and (ii) give functioning as a light verb. We will also discuss aspects of the grammaticalization of SVCs in NGT: from lexical verb to light verb to auxiliary, again offering some comparison to grammaticalization paths described for spoken languages.

Event representations constrain the structure of language: Sign language as a window into universally accessible linguistic biases.

According to a theoretical tradition dating back to Aristotle, verbs can be classified into two broad categories. Telic verbs (e.g., "decide," "sell," "die") encode a logical endpoint, whereas atelic verbs (e.g., "think," "negotiate," "run") do not, and the denoted event could therefore logically continue indefinitely. Here we show that sign languages encode telicity in a seemingly universal way and moreover that even nonsigners lacking any prior experience with sign language understand these encodings. In experiments 1-5, nonsigning English speakers accurately distinguished between telic (e.g., "decide") and atelic (e.g., "think") signs from (the historically unrelated) Italian Sign Language, Sign Language of the Netherlands, and Turkish Sign Language. These results were not due to participants' inferring that the sign merely imitated the action in question. In experiment 6, we used pseudosigns to show that the presence of a salient visual boundary at the end of a gesture was sufficient to elicit telic interpretations, whereas repeated movement without salient boundaries elicited atelic interpretations. Experiments 7-10 confirmed that these visual cues were used by all of the sign languages studied here. Together, these results suggest that signers and nonsigners share universally accessible notions of telicity as well as universally accessible "mapping biases" between telicity and visual form.

Crystallizing Membrane Proteins in the Lipidic Mesophase. Experience with Human Prostaglandin E2 Synthase 1 and an Evolving Strategy.

The lipidic mesophase or in meso method for crystallizing membrane proteins has several high profile targets to its credit and is growing in popularity. Despite its success, the method is in its infancy as far as rational crystallogenesis is concerned. Consequently, significant time, effort, and resources are still required to generate structure-grade crystals, especially with a new target type. Therefore, a need exists for crystallogenesis protocols that are effective with a broad range of membrane protein types. Recently, a strategy for crystallizing a prokaryotic α-helical membrane protein, diacylglycerol kinase (DgkA), by the in meso method was reported (Cryst. Growth. Des.2013, 14, 2846-2857). Here, we describe its application to the human α-helical microsomal prostaglandin E2 synthase 1 (mPGES1). While the DgkA strategy proved useful, significant modifications were needed to generate structure-quality crystals of this important therapeutic target. These included protein engineering, using an additive phospholipid in the hosting mesophase, performing multiple rounds of salt screening, and carrying out trials at 4 °C in the presence of a tight binding ligand. The crystallization strategy detailed here should prove useful for generating structures of other integral membrane proteins by the in meso method.

Structure-based design of thrombin inhibitors.

Despite tremendous efforts by the pharmaceutical industry during the last decade, the prevention of thromboembolic events--the major cause of death in industrialized countries--by efficient anticoagulatory therapy has still not been achieved. One therapeutic strategy focuses on competitive small-molecule thrombin inhibitors, which may block undesirable excessive thrombin activity (conversion of fibrinogen to fibrin and activation of platelet aggregation) and inactivate thrombin in preformed clots. The design of potent tailor-made thrombin inhibitors has been carried out based on structural data; however, the requirements for a target inhibitor, i.e., good pharmacokinetic and physicochemical profiles, still need to be addressed. This constitutes the main challenge in the current quest for a marketable drug, and is the major focus of the developments described in this review.