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 hydrogenbonding to the sulfone group of PVZB1194, whereby L11 moves inwardto the α4/α6 allosteric pocket and moves away from thepocket in absence of the inhibitor. Pharmacophore, three-dimensional(3D)-QSAR, and ADME studies of biphenyl-type inhibitors of Eg5 werealso 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 betweenthe remaining biphenyl-type inhibitors with Eg5. In addition, on thebasis of fragment docking, a structure-based pharmacophore was generated,which shares good overlap of the DHRR features of the pharmacophoremodel DDHRR.6. The structure-based pharmacophore also contains extrahydrogen-bond acceptors and hydrophobic groups, features which providepossibilities in developing new or improved series of compounds.
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