57 research outputs found
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-DielsâAlder reaction between Danishefskyâs 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 factoryâan experiment in collaborative drug discovery
The European Lead Factory (ELF) is a unique collaborative publicâprivate 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 âhonest data brokerâ 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 âdifficultâ
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 Ă
<sup>2</sup>. Moreover, insight from a group of âde novo designedâ
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
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