Analysis of Biphenyl-Type Inhibitors Targeting the Eg5 α4/α6 Allosteric Pocket

Eg5
is a mitotic kinesin protein that plays an important
role in the formation and maintenance of the bipolar spindle during
the mitotic phase. Due to its potentially reduced side effects in
cancer therapy, Eg5 is considered to be an attractive target for developing
anticancer inhibitors. Herein, we report a computational modeling
study involving biphenyl-type inhibitors known to interact with the
α4/α6 allosteric pocket of Eg5. Compared to the well-known
α2/L5/α3 allosteric inhibitors, biphenyl-type inhibitors
show a unique activity profile. In the Eg5–PVZB1194 (a biphenyl-type
inhibitor) crystal structure, loop L11, which is located in the entrance
of the α4/α6 allosteric-binding pocket, is missing due
to crystal-packing effects. To better understand the role of this
flexible loop upon biphenyl-type inhibitor-binding, MD simulations
were performed to observe the L11 conformations from different states.
It was demonstrated that L11 was more stabilized and showed less fluctuation
when PVZB1194 was bound to Eg5. Residue Asn287 from L11 forms hydrogen
bonding to the sulfone group of PVZB1194, whereby L11 moves inward
to the α4/α6 allosteric pocket and moves away from the
pocket in absence of the inhibitor. Pharmacophore, three-dimensional
(3D)-QSAR, and ADME studies of biphenyl-type inhibitors of Eg5 were
also performed. A best pharmacophore model, DDRRH.6, was generated,
having correlation coefficients in the 3D-QSAR study of R2 = 0.81 and Q2 = 0.64. Furthermore,
docking studies were carried out to observe the interaction between
the remaining biphenyl-type inhibitors with Eg5. In addition, on the
basis of fragment docking, a structure-based pharmacophore was generated,
which shares good overlap of the DHRR features of the pharmacophore
model DDHRR.6. The structure-based pharmacophore also contains extra
hydrogen-bond acceptors and hydrophobic groups, features which provide
possibilities in developing new or improved series of compounds.