The TwistDock workflow for evaluation of bivalent Smac mimetics targeting XIAP.

ABSTRACT: Purpose: Mimetics based on Smac, the native inhibitor of XIAP, are promising drug-candidates for the treatment of cancer. Bivalent Smac mimetics inhibit XIAP with even higher potency than monovalent mimetics, but how to optimize the linker that tethers the two monovalent binding motifs remains controversial. Methods: To construct an ensemble of bivalent complex structures for evaluating various linkers, we propose herein a workflow, named TwistDock, consisting of steps of monovalent docking and linker twisting, in which the degrees of freedom are sampled focusing on the rotation of single bonds of the linker. Results: The obtained conformations of bivalent complex distribute randomly in the conformational space with respect to two reaction coordinates introduced by the linker, which are th

SUBMITTER: Huang Q 

PROVIDER: S-EPMC6499140 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature