Charge Density as a Molecular Descriptor to Reveal Differences on High Active Cruzain Inhibitors

Abstract

Available chemotherapy for Chagas disease (CD) involves severe side effects and drugresistance has been observed in some trypanosome strains. Thus, the discovery of new, safer and more effective drugs to treat CD is required (1).Cruzain (Cz), a cysteine protease of the papain-like family, plays a vital role at every stage of the parasite?s life cycle. The active-site region of enzyme is similar to those of other members of the papain superfamily with seven substrate-binding subsites, four (S4, S3, S2, S1) on the acyl side and three (S1′, S2′, S3′) on the amino side of the cleaved substrate bond (2). Currently, 25 inputs associated to this molecular target are registered in the Protein DataBank (rcsb.org), where Cz has been co-crystallized with reversible and irreversible inhibitors.Thereby, Cz presents itself as an interesting target for development of potential therapeutics forthe treatment of the disease by employing a structure-based approach.Among Cz inhibitors, those containing a vinyl sulfone warhead can exhibit good selectivityand a favorable in vivo safety profile despite the irreversible nature of inhibition (1).Jaishankar et al. synthesized and determined the inhibition constant (and binding energies,G) of a series of vinyl sulfone analogs. However, the analysis of key interactions among sub-pockets, that might explain the activity differences between the ligands, is not available yet (3).The quantum theory of atoms in molecules (QTAIM) provides an important insight into the molecular interactions in ligand-receptor (L-R) complexes (4). Through the mapping of the gradient vector field onto the complex charge density, a series of topological elements arise.Among these topological elements, the bond critical point (BCP) and, in particular, the charge density value (ρb) at an interaction BCP is considered as a measure of that interaction strength.Unlike G that is a global property of the entire system, ρb is a local property measured at each interaction BCP. This means that ρb can be used to decompose the binding energy in contributions by groups of atoms (5).Accordingly, the aim of this work was to exploit charge density to decompose total binding energy in contributions by sub-pockets of Cz. In other words, we want to know how strong is the anchoring of known inhibitors to each Cz sub-pocket. This analysis allowed us to identify easily the anchoring points that could be improved (by optimizing inhibitors structure) in order to increaseinhibitor affinity to Cz.