TY - JOUR
T1 - Inhibition of HIV-1 Reverse Transcriptase Dimerization by Small Molecules
AU - Tintori, Cristina
AU - Corona, Angela
AU - Esposito, Francesca
AU - Brai, Annalaura
AU - Grandi, Nicole
AU - Ceresola, Elisa Rita
AU - Clementi, Massimo
AU - Canducci, Filippo
AU - Tramontano, Enzo
AU - Botta, Maurizio
PY - 2016/4/15
Y1 - 2016/4/15
N2 - Because HIV-1 reverse transcriptase is an enzyme whose catalytic activity depends on its heterodimeric structure, this system could be a target for inhibitors that perturb the interactions between the protein subunits, p51 and p66. We previously demonstrated that the small molecule MAS0 reduced the association of the two RT subunits and simultaneously inhibited both the polymerase and ribonuclease H activities. In this study, some analogues of MAS0 were rationally selected by docking studies and evaluated in vitro for their ability to disrupt dimeric assembly. Two inhibitors were identified with improved activity compared to MAS0. This study lays the basis for the rational design of more potent inhibitors of RT dimerization. No going back: Docking simulations exploring a library of commercially available compounds together with biological studies confirm that the tetrahydropyrimido[2,1-f]purinediones scaffold is valuable for the identification of reverse transcriptase dimerization inhibitors with an allosteric mode of action.
AB - Because HIV-1 reverse transcriptase is an enzyme whose catalytic activity depends on its heterodimeric structure, this system could be a target for inhibitors that perturb the interactions between the protein subunits, p51 and p66. We previously demonstrated that the small molecule MAS0 reduced the association of the two RT subunits and simultaneously inhibited both the polymerase and ribonuclease H activities. In this study, some analogues of MAS0 were rationally selected by docking studies and evaluated in vitro for their ability to disrupt dimeric assembly. Two inhibitors were identified with improved activity compared to MAS0. This study lays the basis for the rational design of more potent inhibitors of RT dimerization. No going back: Docking simulations exploring a library of commercially available compounds together with biological studies confirm that the tetrahydropyrimido[2,1-f]purinediones scaffold is valuable for the identification of reverse transcriptase dimerization inhibitors with an allosteric mode of action.
KW - dimerization inhibitors
KW - HIV-1 reverse transcriptase
KW - protein-protein interaction
KW - virtual screening
KW - viruses
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U2 - 10.1002/cbic.201500668
DO - 10.1002/cbic.201500668
M3 - Article
AN - SCOPUS:84962141744
VL - 17
SP - 683
EP - 688
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 8
ER -