Compound Passport Service: supporting corporate collection owners in open innovation.

A growing number of early discovery collaborative agreements are being put in place between large pharma companies and partners in which the rights for assets can reside with a partner, exclusively or jointly. Our corporate screening collection, like many others, was built on the premise that compounds generated in-house and not the subject of paper or patent disclosure were proprietary to the company. Collaborative screening arrangements and medicinal chemistry now make the origin, ownership rights and usage of compounds difficult to determine and manage. The Compound Passport Service is a dynamic database, managed and accessed through a set of reusable services that borrows from social media concepts to allow sample owners to take control of their samples in a much more active way.

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3.

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.

Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation.

Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.

Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- but not ß-inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation.

Two series of inhibitors of type III phosphatidylinositol-4-kinase were identified by high throughput screening and optimised to derive probe compounds that independently and selectively inhibit the α- and the ß-isoforms with no significant activity towards related kinases in the pathway. In a cellular environment, inhibition of the α- but not the ß-subtype led to a reduction in phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate concentration, causing inhibition of inositol-1-phosphate formation and inhibition of proliferation in a panel of cancer cell lines.

A system for encoding and searching Markush structures.

The encoding and searching of generic chemical structures, so-called Markush structures, have received little attention in the literature of late. The ability to encode and search these complex entities is of use in various branches of chemoinformatics. We describe a general language for encoding Markush structures and algorithms for searching them and give three examples of the utility of such a system: development of general Free-Wilson analyses of chemical series, detection of controlled substances within a large database of molecular structures, and searching of large databases of virtual compounds.

Exploiting structural information in patent specifications for key compound prediction.

Patent specifications are one of many information sources needed to progress drug discovery projects. Understanding compound prior art and novelty checking, validation of biological assays, and identification of new starting points for chemical explorations are a few areas where patent analysis is an important component. Cheminformatics methods can be used to facilitate the identification of so-called key compounds in patent specifications. Such methods, relying on structural information extracted from documents by expert curation or text mining, can complement or in some cases replace the traditional manual approach of searching for clues in the text. This paper describes and compares three different methods for the automatic prediction of key compounds in patent specifications using structural information alone. For this data set, the cluster seed analysis described by Hattori et al. (Hattori, K.; Wakabayashi, H.; Tamaki, K. Predicting key example compounds in competitors' patent applications using structural information alone. J. Chem. Inf. Model.2008, 48, 135-142) is superior in terms of prediction accuracy with 26 out of 48 drugs (54%) correctly predicted from their corresponding patents. Nevertheless, the two new methods, based on frequency of R-groups (FOG) and maximum common substructure (MCS) similarity measures, show significant advantages due to their inherent ability to visualize relevant structural features. The results of the FOG method can be enhanced by manual selection of the scaffolds used in the analysis. Finally, a successful example of applying FOG analysis for designing potent ATP-competitive AXL kinase inhibitors with improved properties is described.

The design and synthesis of novel, potent and orally bioavailable N-aryl piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity.

A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-carboxamide, are described.

Better compounds faster: the development and exploitation of a desktop predictive chemistry toolkit.

Today's drug designer has access to vast quantities of data and an impressive array of sophisticated computational methods. At the same time, there is increasing pressure on the pharmaceutical industry to improve its productivity and reduce candidate drug attrition. We set out to develop a highly integrated suite of design and data analysis tools underpinned by the best predictive chemistry methods and models, with the aim of enabling multi-disciplinary compound design teams to make better informed design decisions. In this article we address the challenges of developing a powerful, flexible and user-friendly toolkit, and of maximising its exploitation by the design community. We describe the impact the toolkit has had on drug discovery projects and give our perspective on the future direction of this activity.

Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation.

Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.

Modulators of the human CCR5 receptor. Part 2: SAR of substituted 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides.

SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor.

Directed dihydroxylation of cyclic allylic alcohols and trichloroacetamides using OsO4/TMEDA.

The oxidation of a range of cyclic allylic alcohols and amides with OsO4/TMEDA is presented. Under these conditions, hydrogen bonding control leads to the (contrasteric) formation of the syn isomer in almost every example that was examined. Evidence for the bidentate binding of TMEDA to OsO4 is presented and a plausible mechanism described.