Binding of pyrimidin-2-one ribonucleoside by cytidine deaminase as the transition-state analog 3,4-dihydrouridine and contribution of the 4-hydroxyl group to its binding affinity

Biochemistry ◽  
1989 ◽  
Vol 28 (24) ◽  
pp. 9423-9430 ◽  
Author(s):  
L. Frick ◽  
C. Yang ◽  
V. E. Marquez ◽  
Richard V. Wolfenden
Keyword(s):  
Transition State ◽  
Binding Affinity ◽  
Cytidine Deaminase ◽  
Hydroxyl Group ◽  
Transition State Analog

Transition-state selectivity for a single hydroxyl group during catalysis by cytidine deaminase

Biochemistry ◽  
1995 ◽  
Vol 34 (14) ◽  
pp. 4516-4523 ◽  
Author(s):  
Shibin Xiang ◽  
Steven A. Short ◽  
Richard Wolfenden ◽  
Charles W. Carter
Keyword(s):  
Transition State ◽  
Cytidine Deaminase ◽  
Hydroxyl Group ◽  
State Selectivity

Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV protease

2021 ◽  
Author(s):  
Masahiko Taguchi ◽  
Ryo Oyama ◽  
Masahiro Kaneso ◽  
Shigehiko Hayashi
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Ligand Binding ◽  
Transition State ◽  
Molecular Mechanism ◽  
Binding Affinity ◽  
Free Energy Calculations ◽  
Drug Resistant ◽  
Transition State Analog ◽  
Hiv 1

Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

Cytidine Deaminase. The 2·3 Å Crystal Structure of an Enzyme: Transition-state Analog Complex

1994 ◽  
Vol 235 (2) ◽  
pp. 635-656 ◽  
Author(s):  
Laurie Betts ◽  
Shibin Xiang ◽  
Steven A. Short ◽  
Richard Wolfenden ◽  
Charles W. Carter
Keyword(s):  
Crystal Structure ◽  
Transition State ◽  
Cytidine Deaminase ◽  
Transition State Analog

scholarly journals Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV protease

2021 ◽  
Author(s):  
Masahiko Taguchi ◽  
Ryo Oyama ◽  
Masahiro Kaneso ◽  
Shigehiko Hayashi
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Ligand Binding ◽  
Transition State ◽  
Molecular Mechanism ◽  
Binding Affinity ◽  
Free Energy Calculations ◽  
Drug Resistant ◽  
Transition State Analog ◽  
Hiv 1

Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

scholarly journals Structural Insights into Inhibition of the Acinetobacter-Derived Cephalosporinase ADC-7 by Ceftazidime and Its Boronic Acid Transition State Analog

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Brandy N. Curtis ◽  
Kali A. Smolen ◽  
Sara J. Barlow ◽  
Emilia Caselli ◽  
Fabio Prati ◽  
...  
Keyword(s):  
Transition State ◽  
Boronic Acid ◽  
Carbonyl Oxygen ◽  
Hydroxyl Group ◽  
Side Chain ◽  
Enzyme Complex ◽  
Content Type ◽  
Transition State Analog ◽  
Hydrolysis Of ◽  
Structural Insights

ABSTRACT Extended-spectrum class C β-lactamases have evolved to rapidly inactivate expanded-spectrum cephalosporins, a class of antibiotics designed to be resistant to hydrolysis by β-lactamase enzymes. To better understand the mechanism by which Acinetobacter-derived cephalosporinase-7 (ADC-7), a chromosomal AmpC enzyme, hydrolyzes these molecules, we determined the X-ray crystal structure of ADC-7 in an acyl-enzyme complex with the cephalosporin ceftazidime (2.40 Å) as well as in complex with a boronic acid transition state analog inhibitor that contains the R1 side chain of ceftazidime (1.67 Å). In the acyl-enzyme complex, the carbonyl oxygen is situated in the oxyanion hole where it makes key stabilizing interactions with the main chain nitrogens of Ser64 and Ser315. The boronic acid O1 hydroxyl group is similarly positioned in this area. Conserved residues Gln120 and Asn152 form hydrogen bonds with the amide group of the R1 side chain in both complexes. These complexes represent two steps in the hydrolysis of expanded-spectrum cephalosporins by ADC-7 and offer insight into the inhibition of ADC-7 by ceftazidime through displacement of the deacylating water molecule as well as blocking its trajectory to the acyl carbonyl carbon. In addition, the transition state analog inhibitor, LP06, was shown to bind with high affinity to ADC-7 (Ki, 50 nM) and was able to restore ceftazidime susceptibility, offering the potential for optimization efforts of this type of inhibitor.

ChemInform Abstract: SYNTHESIS OF 1,3-DIAZEPIN-2-ONE NUCLEOSIDES AS TRANSITION-STATE INHIBITORS OF CYTIDINE DEAMINASE

1980 ◽  
Vol 11 (48) ◽  
Author(s):  
V. E. MARQUEZ ◽  
P. S. LIU ◽  
J. A. KELLEY ◽  
J. S. DRISCOLL ◽  
J. J. MCCORMACK
Keyword(s):  
Transition State ◽  
Cytidine Deaminase
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