Targeting Protein Pockets with Halogen Bonds

BOGADO, M. LUCRECIA; VILLAFAÑE, ROXANA N.; ANGELINA, EMILIO; PERUCHENA, NELIDA MARIA

Conferencia; 2nd Women in Bioinformatics & Data Science LA Conference; 2021

women bioinformatic network LA

Halogen bonds (X-bonds) are directional interactions involving an attractive forcebetween an electrophilic region on the halogen and interaction partners withnucleophilic properties, X-bond has gained recognition as an atypical molecularinteraction useful in modeling halogens computationally to develop newpharmaceutical drugs. X-bonds in protein-ligand complexes are surrounded by residuesthat conforms the “X-bond environment”. Since sigma-hole formation in X-bonds is aconsequence of the anisotropy of the charge density distribution around the halogen,protein residues that surround the halogen atom might perturb its charge distributionand X-bond strength. In this work we proposed a protocol to study the feasibility ofprotein pockets to form X-bond with halogenated ligands, based on the environment.First, a structural survey of X-bonded protein-ligand complexes in public databases wasperformed to get a description of the “X-bond environment” based on the chargedensity, with help of the Quantum Theory of Atoms in Molecules (QTAIM). In thesecond step, the “X-bond environment” is used as a reference system to judge thepropensity of protein pockets to host an X-bond. To test the protocol, we generatedposes in which chlorobenzene is forming: (a) the known X-bond and (b) a different Xbond in a nearby protein sub-pocket with no structural evidence about its existence.We termed this last as “decoy X-bond”. Fifty poses were generated with the dockingalgorithm for both known and decoys X-bonds. Charge density-based X-bondenvironments for the docking poses were estimated by mapping the chloro proteinneighborhood, into the X-bond environment pre-computed on the reference system.The protocol was able to prioritize docking poses that reproduce the actual X-bond incrystal structures based on their X-bond environments, since "real X-bonds" havestronger X-bond environments that decoy X-bonds, as expected. The results suggestthat X-bond formation might require a proper protein environment to be established.