TY - JOUR
T1 - Molecular modeling approach to understanding the mode of action of L-nucleosides as antiviral agents
AU - Lee, K.
AU - Chu, C. K.
PY - 2001
Y1 - 2001
N2 - A series of unnatural L-nucleosides such as 3TC, FTC and L-FMAU have been found to be potent antiviral agents. The mode of action of L-nucleosides has been found to be similar to that of D-nucleosides as antiviral agents, despite their unnatural stereochemistry, that is, nucleotide formation by kinases followed by interaction with the reverse transcriptase (RT) of HIV or DNA polymerase. To date, the mode of action of nucleoside inhibitors at the molecular level with respect to the active conformations of the 5′-triphosphates as well as the interaction with the RT is not known. Recently, the X-ray crystal structure of the RT-DNA-dTTP catalytic complex has been reported. Computer modeling has been performed for several pairs of D- and L-nucleoside inhibitors using the HIV-1 RT model and crystal coordinate data from a subset of the protein surrounding the deoxynucleoside triphosphate (dNTP) binding pocket region. Results from our modeling studies of D-/L-zidovudine, D-/L-3TC, D-/L-dideoxycytosine triphosphates, dTTP and dCTP show that their binding energies correlate with the reported 50% effective concentrations. Modeling results are also discussed with respect to favorable conformations of each inhibitor at the dNTP site in the polymerization process. Additionally, the clinically important M184V mutation, which confers resistance against 3TC and FTC, was studied with our modeling system. The binding energy patterns of nucleoside inhibitors at the M184V mutation site correlate with the reported antiviral data.
AB - A series of unnatural L-nucleosides such as 3TC, FTC and L-FMAU have been found to be potent antiviral agents. The mode of action of L-nucleosides has been found to be similar to that of D-nucleosides as antiviral agents, despite their unnatural stereochemistry, that is, nucleotide formation by kinases followed by interaction with the reverse transcriptase (RT) of HIV or DNA polymerase. To date, the mode of action of nucleoside inhibitors at the molecular level with respect to the active conformations of the 5′-triphosphates as well as the interaction with the RT is not known. Recently, the X-ray crystal structure of the RT-DNA-dTTP catalytic complex has been reported. Computer modeling has been performed for several pairs of D- and L-nucleoside inhibitors using the HIV-1 RT model and crystal coordinate data from a subset of the protein surrounding the deoxynucleoside triphosphate (dNTP) binding pocket region. Results from our modeling studies of D-/L-zidovudine, D-/L-3TC, D-/L-dideoxycytosine triphosphates, dTTP and dCTP show that their binding energies correlate with the reported 50% effective concentrations. Modeling results are also discussed with respect to favorable conformations of each inhibitor at the dNTP site in the polymerization process. Additionally, the clinically important M184V mutation, which confers resistance against 3TC and FTC, was studied with our modeling system. The binding energy patterns of nucleoside inhibitors at the M184V mutation site correlate with the reported antiviral data.
UR - http://www.scopus.com/inward/record.url?scp=0035173806&partnerID=8YFLogxK
U2 - 10.1128/AAC.45.1.138-144.2001
DO - 10.1128/AAC.45.1.138-144.2001
M3 - Article
C2 - 11120956
AN - SCOPUS:0035173806
SN - 0066-4804
VL - 45
SP - 138
EP - 144
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 1
ER -