Investigating the SAR of XIAP ligands with Electrostatic Complementarity maps and scores

Electrostatic Complementarity™ maps implemented in Flare™,1 Cresset’s structure-based design application, were used to investigate the protein-ligand electrostatic interactions and the Structure-Activity Relationship (SAR) of a small set of inhibitors of the X-linked IAP (XIAP)-caspase protein-protein interaction. A good correlation was also obtained between XIAP-BIR3 affinity and the Electrostatic Complementarity scores for the same data set.


Inhibitor of apoptosis proteins (IAPs) are key regulators of antiapoptotic and pro-survival signaling pathways.2-4 Their deregulation occurs in various cancers and is associated with tumor growth, resistance to treatment and poor prognosis. This makes them an attractive target for anticancer drug discovery.5-7 The best characterized IAP, X-linked IAP (XIAP), exerts its antiapoptotic activity by binding and inactivation of caspases 3, 7, and 9 via its BIR domains. Disruption of the protein-protein interaction (PPI) between XIAP-BIR domains and caspases via small molecules is a promising strategy to inhibit XIAP. However, drugging PPIs can be particularly challenging due to their unusual binding interfaces, which are unlike classical binding sites generally flat and large.8

A recent paper from Astex9 reports that the XIAP-BIR3 activity of the small dataset of antagonists in Table 1 is increased by the introduction of electron-withdrawing substituents on the indoline ring, and shows a nice correlation between the XIAP-BIR3 pIC50 and Hammett’s σp.

In this case study, we used the Electrostatic Complementarity maps available in Flare to investigate the protein-ligand electrostatic interactions and the SAR of the molecules in Table 1. Electrostatic Complementarity scores calculated with Flare were used to quantitatively model XIAP-BIR3 pIC50.

Electrostatic Complementarity surfaces and scores

Electrostatic Complementarity maps and scoring functions are an extension of Flare’s Protein Interaction Potentials based on Cresset’s polarizable XED force field. In contrast to classical force fields that rely on atom-centered charges, XED enables description of anisotropic charge distribution around atoms which is usually only possible with ab initio approaches. Polarization effects and description of atomic charge anisotropy are especially useful for computing electrostatic properties of aromatic or unsaturated hydrocarbons, sp2 hybridized oxygen atoms, sp or sp2 hybridized nitrogen atoms, and aromatic halogens (sigma hole of Cl, Br, and I).14-16

To calculate the Electrostatic Complementarity map for a ligand towards a protein of interest, the solvent-accessible surface is first placed over the ligand. A calculation of electrostatic potentials due to the ligand and the protein is then carried out at each vertex on the surface.

These potentials are then scaled, added together, and normalized to yield the Electrostatic Complementarity score. Perfect electrostatic complementarity means that at each vertex point the ligand electrostatic potential value is paired with a protein electrostatic potential value of the same magnitude with reverse sign. Regions of the ligand surface where there is electrostatic complementarity with the protein are colored green, while the regions where there is a electrostatic clash are colored red. A more detailed description of the electrostatic potential and complementarity methodology will be presented elsewhere.17

Time Activities / Talks / Seminars Speakers
09:30 Registration
10:30 Closing remarks Mike Shultz, Novartis
11:00 Managing External Chemistry for Effective
Support of Drug Projects
David Hollinshead, Elixir
Software and Andrew Griffin,
Praxis Precision Medicines
12:00 Closing remarks

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