Division of Medicinal Chemistry Abstracts-235th ACS National ...

MEDI 49
Design, synthesis and evaluation of novel azole nucleoside analogs for their activity
against hantaviruses
Sidath C. Kumarapperuma 1 , Marjan Jeselnik 1 , Dong-Hoon Chung 2 , Yanjie Sun 2 , Qianjun Li 2 ,
Yong-Kyu Chu 2 , William B. Parker 2 , Colleen B. Jonsson 2 , and Jeffrey B. Arterburn 1 . (1)
Department of Chemistry and Biochemistry MSC 3C, New Mexico State University, Las Cruces,
NM 88003, Fax: 575-646-2649, sidath@nmsu.edu, (2) Department of Biochemistry and
Molecular Biology, Southern Research Institute, Birmingham, AL 35205
Hantaviruses are tri-segmented negative stranded RNA viruses that are distributed worldwide
and cause two acute febrile diseases in humans: hemorrhagic fever with renal syndrome
(HFRS) and hantavirus pulmonary syndrome (HPS). The nucleoside analog, ribavirin (1-β-Dribofuranosyl-1,2,4-triazole-3-carboxamide),
shows promise in reducing the mortality rate when
administered early following infection. We designed, modeled and synthesized a series of
isosteres, homologated analogs, and substituted derivatives possessing altered steric and
hydrogen-bonding profiles. Since the conversion of ribavirin to the monophosphate by
adenosine kinase (ADK) is the rate-limiting step in the activation of this broad spectrum antiviral
drug, we evaluated these compounds as substrates for ADK and their binding modes with
human ADK using a computational docking study. The antiviral activity of these compounds was
evaluated in vitro against Hantaan virus and Andes virus and in vivo against Hantaan virus. We
have identified a promising new compound that exhibits potent hantaviral antiviral activity.
MEDI 50
Homology modeling and molecular dynamics simulation of Hepatitis B virus DNA
polymerase: Validation using molecular docking
Pankaj R. Daga and Robert J. Doerksen, Department of Medicinal Chemistry, School of
Pharmacy, University of Mississippi, University, MS 38677-1848, Fax: 662-915-5638,
pdaga@olemiss.edu
Hepatitis B is among the top ten infectious diseases in the world. All nucleotide/nucleoside
analogs approved for the treatment of HBV infections target HBV DNA polymerase (HDP). We
built a three-dimensional comparative model of HDP based on an HIV-RT X-ray structure using
multiple alignment followed by minimization, validation and molecular dynamics simulation. The
resultant model demonstrates reasonable stereochemical properties. Further validation was
carried out using docking of known inhibitors such as lamivudine into the active site.
MEDI 51
Design and synthesis of 3-deazaneplanocin A derivatives
Chong Liu and Stewart W. Schneller, Department of Chemistry and Biochemistry, Auburn
University, 179 Chemistry Building, Auburn, AL 36849, Fax: 334-844-0239,
liuchon@auburn.edu, schnest@auburn.edu