Exploration of Human Serum Albumin Binding Sites by Docking and Molecular Dynamics Flexible LigandProtein Interactions
Date
2009-02-09
Authors
Deeb, Omar
Gómez-Castro, Carlos Zepactonal
Garduño-Juárez, Ramón
Correa-Basurto, José
Journal Title
Journal ISSN
Volume Title
Publisher
Wiley Online Library
Abstract
Five-nanosecond molecular dynamics (MD) simulations
were performed on human serum albumin (HSA) to
study the conformational features of its primary ligand
binding sites (I and II). Additionally, 11 HSA snapshots
were extracted every 0.5 ns to explore the binding affinity
(Kd) of 94 known HSA binding drugs using a blind
docking procedure. MD simulations indicate that there is
considerable flexibility for the protein, including the
known sites I and II. Movements at HSA sites I and II
were evidenced by structural analyses and docking
simulations. The latter enabled the study and analysis of
the HSA–ligand interactions of warfarin and ketoprofen
(ligands binding to sites I and II, respectively) in greater
detail. Our results indicate that the free energy values by
docking (Kd observed) depend upon the conformations of
both HSA and the ligand. The 94 HSA–ligand binding
Kd values, obtained by the docking procedure, were
subjected to a quantitative structure-activity relationship
(QSAR) study by multiple regression analysis. The best
correlation between the observed and QSAR theoretical
(Kd predicted) data was displayed at 2.5 ns. This study
provides evidence that HSA binding sites I and II interact
specifically with a variety of compounds through
conformational adjustments of the protein structure in
conjunction with ligand conformational adaptation to
these sites. These results serve to explain the high ligandpromiscuity
of HSA.
Description
Keywords
human serum albumin , molecular dynamics , docking , multiple linear regression analysis