Design, synthesis and biological evaluation of sugar-derived Ras inhibitors

The design and synthesis of novel Ras inhibitors with a bicyclic scaffold derived from the natural sugar D-arabinose are presented. Molecular modelling showed that these ligands can bind Ras by accommodating the aromatic moieties and the phenylhydroxylamino group in a cavity near the Switch II region of the protein. All the synthetic compounds were active in inhibiting nucleotide exchange on p21 human Ras in vitro, and two of them selectively inhibited Ras-dependent cell growth in vivo.     

A Novel Approach to the Discovery of Small-Molecule Ligands of CDK2

In an attempt to identify novel small-molecule ligands of cyclin-dependent kinase 2 (CDK2) with potential as allosteric inhibitors, we have devised a robust and cost-effective fluorescence-based high-throughput screening assay. The assay is based on the specific interaction of CDK2 with the extrinsic fluorophore 8-anilino-1-naphthalene sulfonate (ANS), which binds to a large allosteric pocket adjacent to the ATP site. Hit compounds that displace ANS directly or indirectly from CDK2 are readily classified as ATP site binders or allosteric ligands through the use of staurosporine, which blocks the ATP site without displacing ANS. Pilot screening of 1453 compounds led to the discovery of 12 compounds with displacement activities (EC(50) values) ranging from 6 to 44 μM, all of which were classified as ATP-site-directed ligands. Four new type I inhibitor scaffolds were confirmed by X-ray crystallography. Although this small compound library contained only ATP-site-directed ligands, the application of this assay to large compound libraries has the potential to reveal previously unrecognized chemical scaffolds suitable for structure-based design of CDK2 inhibitors with new mechanisms of action.     

Fueling Open‐Source Drug Discovery: 177 Small‐Molecule Leads against Tuberculosis

With the aim of fuelling open‐source, translational, early‐stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non‐cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead‐generation activities. Two additional drug‐discovery‐relevant datasets are included: a) a drug‐like property analysis reflecting the latest lead‐like guidelines and b) an early lead‐generation package of the most promising hits within the clusters identified.     

Parallel synthesis and fast screening of heterogeneous catalysts

We are presenting an effective method to prepare and test heterogeneous catalysts much faster than by the conventional way. A catalyst array was prepared via an incipient wetness method by combination of different amounts of Pt, Zr, and V on Al₂O₃ by means of an automatic liquid handler. For catalytic testing for methane oxidation a ceramic monolith reactor module, the channels of which contain the different catalyst compositions, was developed in which up to 250 catalyst compositions can be prepared and tested in parallel. Gas samples from each channel of the monolith were analysed sequentially by a mass spectrometer by moving the QMS inlet capillary into the channels using a three-dimensional positioning system which works at high temperatures. By comparison of the testing results with experiments carried out in flow reactors it is shown that the monolithic reactor is an efficient tool for fast screening of heterogeneous catalysts. This revised version was published online in June 2006 with corrections to the Cover Date.     

A Virtual Screening Study of the 18 kDa Translocator Protein using Pharmacophore Models Combined with 3D‐QSAR Studies

In the present study, we considered various pharmacophore hypotheses for TSPO ligands and an optimal one was selected on the basis of 3D‐QSAR studies. This hypothesis was used in a ligand‐based virtual screening study on the Maybridge database with the aim of identifying new TSPO ligands. Binding assays revealed that all selected compounds displayed TSPO affinity at 10 μM , and among them two compounds exhibited sub‐micromolar K_i values. These results validated our applied methodologies, and the two compounds with sub‐micromolar affinity could be used as interesting leads for the development of new active TSPO ligands.     

A Novel Reporter System for Molecular Imaging and High‐Throughput Screening of Anticancer Drugs

Apoptosis is irreversible programmed cell death, characterized by a cellular cascade activation of caspase 3, which subsequently degrades proteins and other components of cells with a motif sequence. Here we report a novel reporter system to detect apoptosis, growth arrest, and cell death based on controlled and self‐amplified protein degradation. The key element of the reporter system is an apoptotic sensor chimerical protein which consists of three components: procaspase 3, ubiquitin (Ub), and a strong consensus sequence of N‐degron. Between each of these units is a DEVD (Asp‐Glu‐Val‐Asp) sequence, which acts as the cleavage target of caspase 3. This non‐conventional signal loss approach is much more sensitive than other native methods that are based on signal gain. The superior sensitivity is demonstrated by its effective application in 386‐well high‐throughput screening (HTS) with low drug concentrations and a short incubation time. The HTS selection process using this reporter system is very simple and economic. The simplicity eliminates potential errors introduced by multiple steps; there is no need for any substrate. Furthermore, the cells in the assay need not be disrupted, and the morphology of the cells can provide additional information on mechanisms. After HTS, the intact cells can also be used for other analytic analysis. This system thus has a potentially important role in the discovery and development of new anticancer drugs. It also appears to be very versatile, can be used both in vitro and in vivo with different linked reporter genes, and can be used for a variety of imaging applications.     

The 12th AFMC International Medicinal Chemistry Symposium (AIMECS 2019) in Istanbul,Turkey

AFMC-AIMECS meetings are internationally organized biannually by the Asian Federation for Medicinal Chemistry (AFMC) and are focused on recent studies in drug discovery and development both in academia and industry. Member organizations of the AFMC are the Pharmaceutical Society of Japan, the Chinese Pharmaceutical Association, the Royal Australian Chemical Institute, the Pharmaceutical Society of Korea, the Korean Chemical Society, the Chemical Society Located in Taipei, the Indonesian Society of Medicinal Chemistry, the Medicinal Chemistry Section of the Israel Chemical Society, and the Computer-Aided Drug Design & Development Society in Turkey. Each time, the symposium is organized within these member countries. The AIMECS 2019 symposium was held in Turkey this year, as Prof. Dr. Esin Aki-Yalcin is the current president of the AFMC (2018–2020); the next AIMECS meeting will be organized in 2021 in Tokyo, Japan. In this report, we discuss key topics at the 12^th AFMC International Medicinal Chemistry Symposium — New Avenues for Design and Development of Translational Medicine (AIMECS 2019) held in Istanbul, September 8–11, 2019.     

Ligand-based virtual screening, parallel solution-phase and microwave-assisted synthesis as tools to identify and synthesize new inhibitors of mycobacterium tuberculosis

In an attempt to identify new inhibitors of the growth of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, a procedure for the generation, design, and screening of a ligand-based virtual library was applied. This used both an in silico protocol centered on a recursive partitioning (RP) model described herein, and a pharmacophoric model for antitubercular agents previously generated by our research group. Two candidates emerged from databases of commercially available compounds, both characterized by a minimum inhibitory concentration (MIC) of 25 microg mL(-1). Based on these compounds, two series of derivatives were synthesized by both parallel solution-phase and microwave-assisted synthesis, leading to enhanced antimycobacterial activity. During both the design and synthesis, attention was focused on the efficient allocation of available resources with the aim of reducing the overall costs associated with calculation and synthesis.     

Design and synthesis of conformationally constrained cyclophilin inhibitors showing a cyclosporin-A phenotype in C. elegans

Cyclophilin A (CypA) is a member of the immunophilin family of proteins and receptor for the immunosuppressant drug cyclosporin A (CsA). Here we describe the design and synthesis of a new class of small-molecule inhibitors for CypA that are based upon a dimedone template. Electrospray mass spectrometry is utilised as an initial screen to quantify the protein affinity of the ligands. Active inhibitors and fluorescently labelled derivatives are then used as chemical probes for investigating the biological role of cyclophilins in the nematode Caenorhabditis elegans.     

Fragment‐Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition

Fragment‐based drug discovery has gained a foothold in today's lead identification processes. We present the application of in silico fragment‐based screening for the discovery of novel lead compounds for the metalloendoproteinase thermolysin. We have chosen thermolysin to validate our screening approach as it is a well‐studied enzyme and serves as a model system for other proteases. A protein‐targeted virtual library was designed and screening was carried out using the program AutoDock. Two fragment hits could be identified. For one of them, the crystal structure in complex with thermolysin is presented. This compound was selected for structure‐based optimization of binding affinity and improvement of ligand efficiency, while concomitantly keeping the fragment‐like properties of the initial hit. Redesigning the zinc coordination group revealed a novel class of fragments possessing K_i values as low as 128 μM , thus they provide a good starting point for further hit evolution in a tailored lead design.     

Drug Discovery Alliances in India—Indications,Targets, and New Chemical Entities

Global pharmaceutical and biotechnology companies have been building increasingly on the skills and services offered by Indian biotech companies through strategic collaborative partnerships and alliances to fuel their in‐house discovery and development pipelines. With the exception of generic press releases, however, very little has been published on the process and progress of drug discovery itself, such as the targets or modes of action involved, nor on the scientific output of such collaborations, and therefore on new chemical entities coming out of India through research collaborations. This Essay provides an analytical review of recent patents, patent applications, and peer‐reviewed publications of major research alliances. It aims at highlighting their scientific output as well as the considerable bandwidth of targets and therapeutic areas involved.     

Hydroxypyridinethione Inhibitors of Human Insulin-Degrading Enzyme

Insulin-degrading enzyme (IDE) is a human mononuclear Zn²⁺-dependent metalloenzyme that is widely regarded as the primary peptidase responsible for insulin degradation. Despite its name, IDE is also critically involved in the hydrolysis of several other disparate peptide hormones, including glucagon, amylin, and the amyloid β-protein. As such, the study of IDE inhibition is highly relevant to deciphering the role of IDE in conditions such as type-2 diabetes mellitus and Alzheimer disease. There have been few reported IDE inhibitors, and of these, inhibitors that directly target the active-site Zn²⁺ ion have yet to be fully explored. In an effort to discover new, zinc-targeting inhibitors of IDE, a library of ∼350 metal-binding pharmacophores was screened against IDE, resulting in the identification of 1-hydroxypyridine-2-thione (1,2-HOPTO) as an effective Zn²⁺-binding scaffold. Screening a focused library of HOPTO compounds identified 3-sulfonamide derivatives of 1,2-HOPTO as inhibitors of IDE (K_i values of ∼50 μM). Further structure-activity relationship studies yielded several thiophene-sulfonamide HOPTO derivatives with good, broad-spectrum activity against IDE that have the potential to be useful pharmacological tools for future studies of IDE.