Protein–protein recognition as a first step towards the inhibition of XIAP and Survivin anti‐apoptotic proteins

Abstract

Apoptosis, also called programmed cell death, is a conserved mechanism inherent to all cells that sentences them to death when they receive the appropriate external stimuli. Inhibitor of apoptosis proteins (IAPs) are a family of regulatory proteins that suppress such cell death. XIAP is the most commonly studied member of the IAP family. It binds to and inhibits Caspases, an important family of apoptotic proteases. In addition, XIAP over-expression has been detected in numerous types of cancer. Smac/DIABLO, a mitochondrial protein that binds to IAPs and promotes Caspase activation, has the opposite action to XIAP and can be considered a key protein in the regulation of IAPs. Survivin, the smallest IAP protein, has received a lot of attention due to its specific expression in many cancer cell lines. It has been shown to interact with Smac/DIABLO, even though the structure of this complex has not yet been reported.We analysed the protein-protein interactions appearing in the Smac/DIABLO-XIAP and Smac/DIABLO-Survivin complexes fully, using molecular dynamics simulations. This information is a first step towards the design of Smac/DIABLO peptidomimetics that could be used as innovative therapeutic agents for the treatment of malignancy. Our results complement the experimental interactions described for the first complex and provide a detailed description for the second. We show that Smac/DIABLO interacts in a similar way with both targets through its amino terminal residues. In addition, we identify a pharmacophore formed by eight stable protein-protein interactions for the XIAP complex and seven stable protein-protein interactions for the Survivin complex, which describe the whole contact surface. This information is used to suggest the binding mode of embelin, the first non-peptidic inhibitor of XIAP, and two of its derivatives. Molecular docking and molecular dynamics simulations were also carried out to describe ligand and receptor flexibility. Finally, an MMGBSA protocol was used to obtain a more quantitative description of the binding in all the complexes studied.

IAP-targeted therapies for cancer

“…Derivatives of embelin have been designed with higher affinity for XIAP BIR3 (for example, compound 6 g, K i ¼ 180 nM) to provide leads for further optimization . Nuclear magnetic resonance and molecular docking analyses confirmed that embelin interacts with several residues in the XIAP BIR3 domain with which Smac and caspase-9 bind (Nikolovska-Coleska et al, 2004;Obiol-Pardo et al, 2008). It remains to be determined whether embelin and its derivatives possess properties similar to SMCs in their ability to produce TNFa, or sensitize cancer cells to exogenous TNFa, and result in the proteosomal loss of cIAP1 and cIAP2.…”

Transient pockets on XIAP-BIR2: toward the characterization of putative binding sites of small-molecule XIAP inhibitors

“…Obiol-Pardo et al also used MD simulations for analyzing the protein-protein interactions appearing in the Smac/Diablo -XIAP complex but they only studied the BIR3 domain [57]. They used the cationic dummy approach [58] for maintaining the tetrahedral coordination of the zinc ion during the simulation while in our simulation, the tetrahedral coordination was preserved through bonded interactions with equilibrium values for angles, dihedrals, and bond lengths taken from a optimized geometry.…”

Diphenyl Urea Derivatives as Inhibitors of Transketolase: A Structure-Based Virtual Screening

“…These compounds were acquired and refined trough a docking-scoring protocol. Docking was performed with our home-made program Dock_Dyn [19] by imposing the pharmacophore constraint to all conformations. This process selects only those conformations that fulfill the pharmacophore restriction speeding up the docking process.…”