A Simple Procedure for Constructing 5'-Amino-Terminated Oligodeoxynucleotides in Aqueous Solution

A rapid method for the synthesis of oligodeoxynucleotides (ODNs) terminated by 5'-amino-5'-deoxythymidine is described. A 3'-phosphorylated ODN (the donor) is incubated in aqueous solution with 5'-amino- 5'-deoxythymidine in the presence of N-(3-dimethylaminopropyl)-)N'-ethylcarbodiimide hydrochloride (EDC), extending the donor by one residue via a phosphoramidate bond. Template- directed ligation of the extended donor and an acceptor ODN, followed by acid hydrolysis, yields the acceptor ODN extended by a single 5'-amino-5'-deoxythymidine residue at its 5'terminus

Recoil velocities from equal-mass binary black-hole mergers: a systematic investigation of spin-orbit aligned configurations

Binary black-hole systems with spins aligned with the orbital angular momentum are of special interest, as studies indicate that this configuration is preferred in nature. If the spins of the two bodies differ, there can be a prominent beaming of the gravitational radiation during the late plunge, causing a recoil of the final merged black hole. We perform an accurate and systematic study of recoil velocities from a sequence of equal-mass black holes whose spins are aligned with the orbital angular momentum, and whose individual spins range from a = +0.584 to -0.584. In this way we extend and refine the results of a previous study and arrive at a consistent maximum recoil of 448 +- 5 km/s for anti-aligned models as well as to a phenomenological expression for the recoil velocity as a function of spin ratio. This relation highlights a nonlinear behavior, not predicted by the PN estimates, and can be readily employed in astrophysical studies on the evolution of binary black holes in massive galaxies. An essential result of our analysis is the identification of different stages in the waveform, including a transient due to lack of an initial linear momentum in the initial data. Furthermore we are able to identify a pair of terms which are largely responsible for the kick, indicating that an accurate computation can be obtained from modes up to l=3. Finally, we provide accurate measures of the radiated energy and angular momentum, finding these to increase linearly with the spin ratio, and derive simple expressions for the final spin and the radiated angular momentum which can be easily implemented in N-body simulations of compact stellar systems. Our code is calibrated with strict convergence tests and we verify the correctness of our measurements by using multiple independent methods whenever possible.Comment: 24 pages, 15 figures, 5 table

Small Molecule-Protein Interactions

Based on the international workshop on 'Small Molecule - Protein Interactions' held in Berlin, April 24-26, 2002, researchers from industry and academic laboratories describe novel and efficient ways selecting promising new drug targets and developing small molecule inhibitors against them. The structure of the book corresponds to the different aspects of the drug discovery process. All chapters are written by leading experts in the field, who present and discuss the most recent state-of-the-art tools and techniques for the development of novel drugs. The value of the book lies in surveying and summarizing the approaches taken by different companies and institutions giving the reader a balanced view on the use of the latest techniques on the one hand and experience-based assistance in selecting appropriate tools for their own work on the other hand.G. Wess: Drug Discovery Opportunities; A.L. Hopkins / C.R. Groom: Target Analysis: a priori Assessment and Drugability; J. Wells: Site-Directed Drug Discovery at Signaling Interfaces; T. Willson: Chemical Genomics of Orphan Nuclear Receptors; H. Jhoti: High-Throughput X-ray Techniques and Drug Discovery; H. Kessler et al.: NMR in Medicinal Chemistry; M.F.M. Engels: Creating Knowledge from High-Throughput Screening Data; G. Klebe: From Structure to Recognition Principles: Mining in Cystal Data as a Prerequisite for Drug Design; M. Stahl / T. Schulz-Gasch: Practical Database Screening with Docking Tools; H. Briem: De novo Design Methods; R. Breinbauer et al.: From Protein Domains to Drug Candidates - Natural Products as Guiding Principles in Compound Library Design and Synthesis; L. Weber: Discovery of new MCR's, Chemical Evolution and Lead Optimization; P.H.H. Hermkens / G. Müller: The Impact of Combinatorial Chemistry on Drug Discovery

Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase

Inhibition of monopolar spindle 1 MPS1 kinase represents a novel approach to cancer treatment instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series triazolopyridines and imidazopyrazines . The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10 fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy model