The universal expression for the amplitude square in quantum electrodynamics

The universal expression for the amplitude square |u_f M u_i|^2 for any matrix of interaction M is derived. It has obvious covariant form. It allows the avoidance of calculation of products of the Dirac's matrices traces and allows easy calculation of cross-sections of any different processes with polarized and unpolarized particles.Comment: 4 page

On evaluating moleculardocking methods for pose prediction and enrichment factors.

Four of the most well-known, commercially available docking programs, FlexX, GOLD, GLIDE, and ICM, have been examined for their ligand-docking and virtual-screening capabilities. The relative performance of the programs in reproducing the native ligand conformation from starting SMILES strings for 164 highresolution protein-ligand complexes is presented and compared. Applying only the native scoring functions, the latest versions of these four docking programs were also used to conduct virtual screening for 12 protein targets of therapeutic interest, involving both publicly available structures and AstraZeneca in-house structures. The capability of the four programs to correctly rank-order target-specific active compounds over alternative binders and nonbinders (decoys plus randomly selected compounds) and thereby enrich a small subset of a screening library is compared. Enrichments from the virtual-screening experiments are contrasted with those obtained with alternative 3D shape-matching and 2D similarity database-search methods

Stereoselective synthesis of a natural product inspired tetrahydroindolo[2,3-a]-quinolizine compound library

AbstractA natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3-a]quinolizine scaffold was established with a five step synthesis route. An imino-Diels–Alder reaction between Danishefsky’s diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold. Thus a compound library of 530 tetrahydroindolo[2,3-a]quinolizines was generated and submitted to European lead factory consortium for various biological screenings

DPD-inspired discovery of novel LsrK kinase inhibitors: an opportunity to fight antimicrobial resistance

Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the past decade, the interference with bacterial quorum sensing (QS) (i.e., cell cell communication) mechanisms has extensively been investigated as a valid therapeutic approach in the pursuit of a next generation of antimicrobials. (S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as (S)-DPD, a small signaling molecule that modulates QS in both Gram-negative and Gram-positive bacteria, is phosphorylated by LsrK, and the resulting phospho-DPD activates QS. We designed and prepared a small library of DPD derivatives, characterized by five different scaffolds, and evaluated their LsrK inhibition in the context of QS interference. SAR studies highlighted the pyrazole moiety as an essential structural element for LsrK inhibition. Particularly, four compounds were found to be micromolar LsrK inhibitors (IC50 ranging between 100 mu M and 500 mu M) encouraging further exploration of novel analogues as potential new antimicrobials.Peer reviewe

The European lead factory—an experiment in collaborative drug discovery

The European Lead Factory (ELF) is a unique collaborative public–private partnership aiming to deliver innovative drug discovery starting points and improving the value generated by ultra-High Throughput Screening (uHTS) approaches. Composed of a unique compound collection derived from private pharmaceutical company collections and complemented with new chemistries from a unique public collection, it offers a unique uHTS platform accessible to both private companies and publicly funded researchers. One of the key challenges in setting up ELF has been to balance access to screening results with protecting the value of compounds in the collection. Through an ‘honest data broker’ data management platform and a royalty reward scheme based on achieved milestones, ELF has been able to overcome these challenges. Set up in 2013, it has already accepted 42 targets for screening, submitted by publicly funded researchers, and generated 12 Qualified Hit Lists. In addition, 55,000 new library compounds have been generated by the public partners and added to the 320,000 compounds made available by the companies. Although it faced many challenges in becoming operational, this unique experiment in collaboration is already generating exciting results that will hopefully, eventually lead to better medicines and tools to advance our biological knowledge, and should act as a template for future approaches in the area

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes

Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties?

Macrocycles are ideal in efforts to tackle “difficult” targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (<i>N</i> = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 Ų. Moreover, insight from a group of “de novo designed” oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space

Apoptosis-inducing factor: vital and lethal

International audienceApoptosis-inducing factor (AIF) is a NADH oxidase with a local redox function that is essential for optimal oxidative phosphorylation and for an efficient anti-oxidant defense. The absence of AIF can cause neurodegeneration, skeleton muscle atrophy and dilated cardiomyopathy. In many models of apoptosis, AIF translocates to the nucleus, where it induces chromatin condensation and DNA degradation. The nuclear localization of AIF can be inhibited by blocking upstream signals of apoptosis. The contribution of AIF to cell death depends on the cell type and apoptotic insult and is only seen when caspases are inhibited or not activated. It is unknown to what extent and through which mechanisms AIF contributes to the induction of cell death. Here, we discuss recent progress in the quest to understand the contribution of AIF to life and death

Intramolecular Hydrogen Bond Expectations in Medicinal Chemistry

Design strategies centered on intramolecular hydrogen bonds are sometime used in drug discovery, but their general applicability has not been addressed beyond scattered examples or circumstantial evidence. A total of 1053 matched molecular pairs where only one of the two molecules is able to form an intramolecular hydrogen bond via monatomic transformations have been identified across the ChEMBL database. These pairs were used to investigate the effect of intramolecular hydrogen bonds on biological activity. While cases of extreme, conflicting variation of effect emerge, the mean biological activity difference for a pair is close to zero and does not exceed ±0.5 log biological activity for over 50% of the analyzed sample