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

Available chemotherapy for Chagas disease (CD) involves severe side effects and drug- resistance 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...

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Autores principales: Luchi, Adriano Martín, Bogado, María Lucrecia, Villafañe, Roxana Noelia, Angelina, Emilio Luis, Peruchena, Nélida María
Formato: Congreso
Lenguaje:Inglés
Publicado: Consejo Nacional De Investigaciones Científicas Y Técnicas 2025
Materias:
Chagas
Parasite’s
Chemotherapy
Acceso en línea:http://repositorio.unne.edu.ar/handle/123456789/56431
Aporte de:
RIUNNE - Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) de Universidad Nacional del Nordeste
id I48-R184-123456789-56431
record_format dspace
spelling I48-R184-123456789-564312025-03-06T11:31:50Z Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors Luchi, Adriano Martín Bogado, María Lucrecia Villafañe, Roxana Noelia Angelina, Emilio Luis Peruchena, Nélida María Chagas Parasite’s Chemotherapy Available chemotherapy for Chagas disease (CD) involves severe side effects and drug- resistance 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 Data Bank (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 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 vivo safety 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 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 ΔG 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 increase inhibitor affinity to Cz. 2025-02-19T18:35:27Z 2025-02-19T18:35:27Z 2018-12-06 Congreso Luchi, Adriano Martín, 2018. Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors. En: Drug Discovery for Neglected Diseases International Congress 2018. Buenos Aires: Consejo Nacional De Investigaciones Científicas Y Técnicas; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de la Química y Metabolismo del Fármaco, p. 252-256. 978-987-47034-0-8 http://repositorio.unne.edu.ar/handle/123456789/56431 eng openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ application/pdf p. 252-256 application/pdf Consejo Nacional De Investigaciones Científicas Y Técnicas Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de la Química y Metabolismo del Fármaco
institution Universidad Nacional del Nordeste
institution_str I-48
repository_str R-184
collection RIUNNE - Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE)
language Inglés
topic Chagas
Parasite’s
Chemotherapy
spellingShingle Chagas
Parasite’s
Chemotherapy
Luchi, Adriano Martín
Bogado, María Lucrecia
Villafañe, Roxana Noelia
Angelina, Emilio Luis
Peruchena, Nélida María
Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors
topic_facet Chagas
Parasite’s
Chemotherapy
description Available chemotherapy for Chagas disease (CD) involves severe side effects and drug- resistance 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 Data Bank (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 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 vivo safety 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 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 ΔG 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 increase inhibitor affinity to Cz.
format Congreso
author Luchi, Adriano Martín
Bogado, María Lucrecia
Villafañe, Roxana Noelia
Angelina, Emilio Luis
Peruchena, Nélida María
author_facet Luchi, Adriano Martín
Bogado, María Lucrecia
Villafañe, Roxana Noelia
Angelina, Emilio Luis
Peruchena, Nélida María
author_sort Luchi, Adriano Martín
title Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors
title_short Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors
title_full Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors
title_fullStr Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors
title_full_unstemmed Charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors
title_sort charge density as a molecular descriptor to reveal differences on high active cruzain inhibitors
publisher Consejo Nacional De Investigaciones Científicas Y Técnicas
publishDate 2025
url http://repositorio.unne.edu.ar/handle/123456789/56431
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AT angelinaemilioluis chargedensityasamoleculardescriptortorevealdifferencesonhighactivecruzaininhibitors
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