Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors

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

Buenos Aires

Congreso; Drug Discovery for Neglected Diseases International Congress 2018; 2018

CONSEJO NACIONAL DE INVESTIGACIONES CIENTÍFICAS Y TÉCNICASFACULTAD DE FARMACIA Y BIOQUÍMICA UNIVERSIDAD DE BUENOS AIRES

Available chemotherapy for Chagas disease (CD) involves severe side effects and drug- resistance has been observedin 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 substratebindingsubsites, four (S4, S3, S2, S1) on the acyl side and three (S1′, S2′, S3′) on the amino side of the cleavedsubstrate bond [2].Currently, 25 inputs associated to this molecular target are registered in the Protein Data Bank (rcsb.org), where Czhas been co-crystallized with reversible and irreversible inhibitors. Thereby, Cz presents itself as an interesting targetfor development of potential therapeutics for the treatment of the disease by employing a structure-based approach.Among Cz inhibitors, those containing a vinyl sulfone warhead can exhibit good selectivity and a favorable in vivosafety profile despite the irreversible nature of inhibition [1].Jaishankar et al. synthesized and determined the inhibition constant (and binding energies, ΔG) of a series of vinylsulfone analogs. However, the analysis of key interactions among sub-pockets, that might explain the activitydifferences between the ligands, is not available yet [3].The quantum theory of atoms in molecules (QTAIM) provides an important insight into the molecular interactions inligand-receptor (L-R) complexes [4]. Through the mapping of the gradient vector field onto the complex charge density, aseries 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 ΔG that is a global property of the entire system, ρb is a local property measured at each interaction BCP. Thismeans 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 contributionsby sub-pockets of Cz. In other words, we want to know how strong is the anchoring of known inhibitors to each Czsub-pocket. This analysis allowed us to identify easily the anchoring points that could be improved (by optimizinginhibitors structure) in order to increase inhibitor affinity to Cz.