Distinguishing binders from false positives by free energy calculations: fragment
screening against the flap site of HIV protease
#MMPMID25189630
Deng N
; Forli S
; He P
; Perryman A
; Wickstrom L
; Vijayan RS
; Tiefenbrunn T
; Stout D
; Gallicchio E
; Olson AJ
; Levy RM
J Phys Chem B
2015[Jan]; 119
(3
): 976-88
PMID25189630
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Molecular docking is a powerful tool used in drug discovery and structural
biology for predicting the structures of ligand-receptor complexes. However, the
accuracy of docking calculations can be limited by factors such as the neglect of
protein reorganization in the scoring function; as a result, ligand screening can
produce a high rate of false positive hits. Although absolute binding free energy
methods still have difficulty in accurately rank-ordering binders, we believe
that they can be fruitfully employed to distinguish binders from nonbinders and
reduce the false positive rate. Here we study a set of ligands that dock
favorably to a newly discovered, potentially allosteric site on the flap of HIV-1
protease. Fragment binding to this site stabilizes a closed form of protease,
which could be exploited for the design of allosteric inhibitors. Twenty-three
top-ranked protein-ligand complexes from AutoDock were subject to the free energy
screening using two methods, the recently developed binding energy analysis
method (BEDAM) and the standard double decoupling method (DDM). Free energy
calculations correctly identified most of the false positives (?83%) and
recovered all the confirmed binders. The results show a gap averaging ?3.7
kcal/mol, separating the binders and the false positives. We present a formula
that decomposes the binding free energy into contributions from the receptor
conformational macrostates, which provides insights into the roles of different
binding modes. Our binding free energy component analysis further suggests that
improving the treatment for the desolvation penalty associated with the
unfulfilled polar groups could reduce the rate of false positive hits in docking.
The current study demonstrates that the combination of docking with free energy
methods can be very useful for more accurate ligand screening against valuable
drug targets.
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