S4MPLE – Sampler For Multiple Protein–Ligand Entities: Simultaneous Docking of Several Entities

S4MPLE is a conformational sampling tool, based on a
hybrid genetic
algorithm, simulating one (conformer enumeration) or more molecules
(docking). Energy calculations are based on the AMBER force field
[Cornell et al. J. Am. Chem.
Soc. 1995, 117, 5179.] for biological macromolecules and its generalized version
GAFF [Wang et al. J. Comput.
Chem. 2004, 25, 1157.] for ligands. This paper describes more advanced, specific
applications of S4MPLE to problems more complex than classical redocking
of drug-like compounds [Hoffer et
al. J. Mol. Graphics Modell. 2012, submitted
for publication.]. Here, simultaneous docking of multiple
entities is addressed in two different important contexts. First,
simultaneous docking of two fragment-like ligands was attempted, as
such ternary complexes are the basis of fragment-based drug design
by linkage of the independent binders. As a preliminary, the capacity
of S4MPLE to dock fragment-like compounds has been assessed, since
this class of small probes used in fragment-based drug design covers
a different chemical space than drug-like molecules. Herein reported
success rates from fragments redocking are as good as classical benchmarking
results on drug-like compounds (Astex Diverse Set [Hartshorn et al. J. Med. Chem. 2007, 50, 726.]). Then, S4MPLE is successfully challenged to predict locations
of fragments involved in ternary complexes by means of multientity
docking. Second, the key problem of predicting water-mediated interaction
is addressed by considering explicit water molecules as additional
entities to be docked in the presence of the “main”
ligand. Blind prediction of solvent molecule positions, reproducing
relevant ligand-water-site mediated interactions, is achieved in 76%
cases over saved poses. S4MPLE was also successful to predict crystallographic
water displacement by a therefore tailored functional group in the
optimized ligand. However, water localization is an extremely delicate
issue in terms of weighing of electrostatic and desolvation terms
and also introduces a significant increase of required sampling efforts.
Yet, the herein reported results – not making use of massively
parallel deployment of the software – are very encouraging.