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Scapin G.,Merck And Co.
Acta Crystallographica Section D: Biological Crystallography | Year: 2013

The 'phase problem' in crystallography results from the inability to directly measure the phases of individual diffracted X-ray waves. While intensities are directly measured during data collection, phases must be obtained by other means. Several phasing methods are available (MIR, SAR, MAD, SAD and MR) and they all rely on the premise that phase information can be obtained if the positions of marker atoms in the unknown crystal structure are known. This paper is dedicated to the most popular phasing method, molecular replacement (MR), and represents a personal overview of the development, use and requirements of the methodology. The first description of noncrystallographic symmetry as a tool for structure determination was explained by Rossmann and Blow [Rossmann & Blow (1962), Acta Cryst. 15, 24-31]. The term 'molecular replacement' was introduced as the name of a book in which the early papers were collected and briefly reviewed [Rossmann (1972), The Molecular Replacement Method. New York: Gordon & Breach]. Several programs have evolved from the original concept to allow faster and more sophisticated searches, including six-dimensional searches and brute-force approaches. While careful selection of the resolution range for the search and the quality of the data will greatly influence the outcome, the correct choice of the search model is probably still the main criterion to guarantee success in solving a structure using MR. Two of the main parameters used to define the 'best' search model are sequence identity (25% or more) and structural similarity. Another parameter that may often be undervalued is the quality of the probe: there is clearly a relationship between the quality and the correctness of the chosen probe and its usefulness as a search model. Efforts should be made by all structural biologists to ensure that their deposited structures, which are potential search probes for future systems, are of the best possible quality. Source


Schonherr H.,Columbia University | Cernak T.,Merck And Co.
Angewandte Chemie - International Edition | Year: 2013

The methyl group is one of the most commonly occurring carbon fragments in small-molecule drugs. This simplest alkyl fragment appears in more than 67 % of the top-selling drugs of 2011 and can modulate both the biological and physical properties of a molecule. This Review focuses on so-called magic methyl effects on binding potency, where the seemingly mundane change of C-H to C-Me improves the IC50 value of a drug candidate more than 100-fold. This discussion is followed by a survey of recent advances in synthetic chemistry that allow the direct methylation of C(sp2)-H and C(sp3)-H bonds. It is our hope that the relevance of the meager methyl group to drug discovery as presented herein will inspire reports on new C-H methylation reactions. It′s a kind of magic: The methyl group is one of the most prominent functional groups in bioactive small molecules and appears in more than 67 % of the top-selling drugs. This Review highlights examples of the magic methyl effect, whereby the installation of a single methyl group boosts potency by more than two orders of magnitude. New C-H activation reactions are required to facilitate the direct introduction of methyl groups. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Roemer T.,Merck And Co. | Boone C.,University of Toronto
Nature Chemical Biology | Year: 2013

Here, we review the 'target-centric' genomic strategy to antimicrobial discovery and share our perspective on identification, validation and prioritization of potential antimicrobial drug targets in the context of emerging chemical biology, genomics and phenotypic screening strategies. We propose that coupling the dual processes of antimicrobial small-molecule screening and target identification in a whole-cell context is essential to empirically annotate 'druggable' targets and advance early stage antimicrobial discovery. We also advocate a systems-level approach to annotating synthetic-lethal genetic interactions comprehensively within yeast and bacteria models. The resulting genetic interaction networks provide a landscape to rationally predict and exploit drug synergy between cognate inhibitors. We posit that synergistic combination agents provide an important and largely unexploited strategy to 'repurpose' existing chemical space and simultaneously address issues of potency, spectrum, toxicity and drug resistance in early stages of antimicrobial drug discovery. © 2013 Nature America, Inc. All rights reserved. Source


Hazuda D.J.,Merck And Co.
Current Opinion in HIV and AIDS | Year: 2012

PURPOSE OF REVIEW: Integrase strand transfer inhibitors are the most recent class of antiretroviral agents to be introduced into clinical practice. This review describes the discovery of the first inhibitors and insights into their distinct mechanism of action with potential translational implications. RECENT FINDINGS: HIV replication depends on the successful integration of the viral genetic material into the host cell chromosome. The virally encoded enzyme integrase mediates both the DNA cutting and strand transfer or DNA joining steps which are required for this process. Understanding the mechanistic aspects of integration was critical for the initial discovery of integrase strand transfer inhibitors and the advancement of clinical candidates. The recent adoption of these inhibitors into clinic practice has now proven the therapeutic utility of the class. Integrase inhibitors are characterized by a more rapid decrease in viral load in HIV-1-infected patients initiating therapy and possess prolonged window for intervention in the viral life cycle, thus offering an advantage in the setting of HIV-1 chemoprevention. SUMMARY: The distinct biochemical and antiviral mechanism of action of integrase strand transfer inhibitors are directly relevant to understanding the clinical properties which are characteristic of the class and their potential significance for the use of these agents in both treatment and prevention. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Lin H.V.,Merck And Co. | Accili D.,Columbia University
Cell Metabolism | Year: 2011

We review mechanisms that regulate production of glucose by the liver, focusing on areas of budding consensus, and endeavoring to provide a candid assessment of lingering controversies. We also attempt to reconcile data from tracer studies in humans and large animals with the growing compilation of mouse knockouts that display changes in glucose production. A clinical hallmark of diabetes, excessive glucose production remains key to its treatment. Hence, we attempt to integrate emerging pathways into the broader goal to rejuvenate the staid antidiabetic pharmacopeia. © 2011 Elsevier Inc. Source

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