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

ACS Omega
Chunxia GaoLeif A Eriksson

Abstract

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-di...Continue Reading

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Citations

Apr 19, 2019·Pharmaceuticals·Tomisin Happy OgunwaTakayuki Miyanishi

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Methods Mentioned

BETA
xenograft

Software Mentioned

Phase
Schrödinger
AMBER10
Prime
GROMACS
QikProp
Receptor Grid Generation panel
Maestro
OPLS
ConfGen

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