Homology models of the HIV-1 attachment inhibitor BMS-626529 bound to gp120 suggest a unique mechanism of action.
HIV-1 gp120 undergoes multiple conformational changes both before and after binding to the host CD4 receptor. BMS-626529 is an attachment inhibitor (AI) in clinical development (administered as prodrug BMS-663068) that binds to HIV-1 gp120. To investigate the mechanism of action of this new class of antiretroviral compounds, we constructed homology models of unliganded HIV-1 gp120 (UNLIG), a pre-CD4 binding-intermediate conformation (pCD4), a CD4 bound-intermediate conformation (bCD4), and a CD4/co-receptor-bound gp120 (LIG) from a series of partial structures. We also describe a simple pathway illustrating the transition between these four states. Guided by the positions of BMS-626529 resistance substitutions and structure-activity relationship data for the AI series, putative binding sites for BMS-626529 were identified, supported by biochemical and biophysical data. BMS-626529 was docked into the UNLIG model and molecular dynamics simulations were used to demonstrate the thermodynamic stability of the different gp120 UNLIG/BMS-626529 models. We propose that BMS-626529 binds to the UNLIG conformation of gp120 within the structurally conserved outer domain, under the antiparallel β20-β21 sheet, and adjacent to the CD4 binding loop. Through this binding mode, BMS-626529 can inhibit both CD4-induced and CD4-independent formation of the "open state" four-stranded gp120 bridging sheet, and the subsequent formation and exposure of the chemokine co-receptor binding site. This unique mechanism of action prevents the initial interaction of HIV-1 with the host CD4+ T cell, and subsequent HIV-1 binding and entry. Our findings clarify the novel mechanism of BMS-626529, supporting its ongoing clinical development.
Computer Assisted Drug Design, Bristol-Myers Squibb, Research and Development, Wallingford, Connecticut.
David R
DR
Langley
S Roy
SR
Kimura
Prasanna
P
Sivaprakasam
Nannan
N
Zhou
Ira
I
Dicker
Brian
B
McAuliffe
Tao
T
Wang
John F
JF
Kadow
Nicholas A
NA
Meanwell
Mark
M
Krystal
D001665:Binding Sites; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D023581:HIV Fusion Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
C584152:BMS-626529; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D014230:Triazoles; C514793:gp120 protein, Human immunodeficiency virus 1
antiretroviral; molecular dynamics; protein modeling