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Ramamoorthy D.,University of South Florida | Turos E.,University of South Florida | Turos E.,Center for Molecular Diversity in Drug Design | Turos E.,Center for Drug Discovery and Innovation | And 4 more authors.
Journal of Chemical Information and Modeling | Year: 2013

FabH (Fatty acid biosynthesis, enzyme H, also referred to as β-ketoacyl-ACP-synthase III) is a key condensing enzyme in the type II fatty acid synthesis (FAS) system. The FAS pathway in bacteria is essential for growth and survival and vastly differs from the human FAS pathway. Enzymes involved in this pathway have arisen as promising biomolecular targets for discovery of new antibacterial drugs. However, currently there are no clinical drugs that selectively target FabH, and known inhibitors of FabH all act within the active site. FabH exerts its catalytic function as a dimer, which could potentially be exploited in developing new strategies for inhibitor design. The aim of this study was to elucidate structural details of the dimer interface region by means of computational modeling, including molecular dynamics (MD) simulations, in order to derive information for the structure-based design of new FabH inhibitors. The dimer interface region was analyzed by MD simulations, trajectory snapshots were collected for further analyses, and docking studies were performed with potential small molecule disruptors. Alanine mutation and docking studies strongly suggest that the dimer interface could be a potential target for anti-infection drug discovery. © 2013 American Chemical Society. Source


Lebar M.D.,Center for Molecular Diversity in Drug Design | Baker B.J.,Center for Molecular Diversity in Drug Design
Tetrahedron | Year: 2010

Palmerolide A, a potent and selective inhibitor of melanoma cell growth, is a macrocylic polyketide isolated from the Antarctic tunicate Synoicum adareanum. Palmerolide A targets transmembrane proton pumps, the vacuolar-ATPases, and induces autophagy, but in a manner independent of HIF-1α activation. Herein we report a synthesis of the C3-14 fragment of palmerolide A using readily available polyols as chiral building blocks for entry into structure/activity studies of the macrocycle. © 2009. Source


Lebar M.D.,Center for Molecular Diversity in Drug Design | Hahn K.N.,Center for Molecular Diversity in Drug Design | Mutka T.,University of South Florida | Maignan P.,University of South Florida | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

The marine invertebrate-derived meridianin A, the originally proposed structure for psammopemmin A, and several related 3-pyrimidylindole analogs were synthesized and subsequently investigated for central nervous system, antimalarial, and cytotoxic activity. A Suzuki coupling of an indoleborate ester to the pyrimidine electrophile was utilized to form the natural product and derivatives thereof. The 3-pyrimidineindoles were found to prevent radioligand binding to several CNS receptors and transporters, most notably, serotonin receptors (<0.2 μM K i for 5HT 2B). Two compounds also inhibited the human malaria parasite Plasmodium falciparum (IC 50 <50 μM). Only the natural product was cytotoxic toward A549 cells (IC 50 = 15 μM). © 2011 Elsevier Ltd. All rights reserved. Source

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