Luciana Gavernet - Academia.edu (original) (raw)

Papers by Luciana Gavernet

Polish Journal of Chemistry, 1999

Chemistry & Biodiversity, Dec 16, 2021

Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation a... more Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation and osmotic regulation of trypanosomatids; in some trypanosomatid species, they have been validated as molecular targets for the development of new therapeutic agents. Because the experimental structure of Trypanosoma cruzi PDEb1 (TcrPDEb1) has not been solved so far, an homology model of the target was created using the structure of Trypanosoma brucei PDEb1 (TbrPDEb1) as a template. The model was refined by extensive enhanced sampling molecular dynamics simulations, and representative snapshots were extracted from the trajectory by combined clustering analysis. This structural ensemble was used to develop a structure‐based docking model of the target. The docking accuracy of the model was validated by redocking and cross‐docking experiments using all available crystal structures of TbrPDEb1, whereas the scoring accuracy was validated through a retrospective screen, using a carefully curated dataset of compounds assayed against TbrPDEb1 and/or TcrPDEb1. Considering the results from in silico validations, the model may be applied in prospective virtual screening campaigns to identify novel hits, as well as to guide the rational design of potent and selective inhibitors targeting this enzyme.

Bioorganic & Medicinal Chemistry, Aug 1, 2007

A series of new xanthone derivatives have been synthesized and evaluated for their anticonvulsant... more A series of new xanthone derivatives have been synthesized and evaluated for their anticonvulsant properties in the maximal electroshock (MES), subcutaneous metrazole (ScMet) tests as well as for neurotoxicity in the rotarod (TOX) in mice, i.p. and rats, p.o. Compound 9: R,S-2-{2-[(1-hydroxybutan-2-yl]amino)ethoxy}-9H-xanthen-9-one and compound 12: R,S-2-{3-[(1-hydroxybutan-2-yl)amino]propoxy}-9H-xanthen-9-one exerted activity in rats, p.o. 2 and 4 h after administration, respectively. Therefore, metabolic stability of the compounds was evaluated with use of rats microsomes, resulting in half-life t 1/2 136 and 108 min, respectively, indicating that either the metabolites are very active, or the parent compounds exert other ADME properties other than metabolism which influence the late onset of activity.

Journal of Enzyme Inhibition and Medicinal Chemistry, 2019

In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide... more In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED 50 ¼ 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).

Journal of Chemical Information and Modeling, May 19, 2010

BENTHAM SCIENCE PUBLISHERS eBooks, Jul 2, 2012

European Journal of Chemistry, Mar 31, 2013

Kinetic study of benzyl sulfamide synthesis by thermolysis of N-(benzyl)-N´-(tert-butoxycarbolyl)... more Kinetic study of benzyl sulfamide synthesis by thermolysis of N-(benzyl)-N´-(tert-butoxycarbolyl) sulfamide

Journal of Chemical Information and Modeling, Jun 27, 2022

Journal of Chemical Information and Modeling, Jul 27, 2021

The scientific community is working against the clock to arrive at therapeutic interventions to t... more The scientific community is working against the clock to arrive at therapeutic interventions to treat patients with COVID-19. Among the strategies for drug discovery, virtual screening approaches have the capacity to search potential hits within millions of chemical structures in days, with the appropriate computing infrastructure. In this article, we first analyzed the published research targeting the inhibition of the main protease (Mpro), one of the most studied targets of SARS-CoV-2, by docking-based methods. An alarming finding was the lack of an adequate validation of the docking protocols (i.e., pose prediction and virtual screening accuracy) before applying them in virtual screening campaigns. The performance of the docking protocols was tested at some level in 57.7% of the 168 investigations analyzed. However, we found only three examples of a complete retrospective analysis of the scoring functions to quantify the virtual screening accuracy of the methods. Moreover, only two publications reported some experimental evaluation of the proposed hits until preparing this manuscript. All of these findings led us to carry out a retrospective performance validation of three different docking protocols, through the analysis of their pose prediction and screening accuracy. Surprisingly, we found that even though all tested docking protocols have a good pose prediction, their screening accuracy is quite limited as they fail to correctly rank a test set of compounds. These results highlight the importance of conducting an adequate validation of the docking protocols before carrying out virtual screening campaigns, and to experimentally confirm the predictions made by the models before drawing bold conclusions. Finally, successful structure-based drug discovery investigations published during the redaction of this manuscript allow us to propose the inclusion of target flexibility and consensus scoring as alternatives to improve the accuracy of the methods.

Frontiers in Pharmacology

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication... more Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Res...

Journal of Computer-Aided Molecular Design

Journal of Chemical Information and Modeling

Polish Journal of Chemistry, 1999

European Journal of Medicinal Chemistry, 2018

Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old dru... more Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old drugs, benznidazole and nifurtimox, which have restricted efficacy against the chronic phase of the illness. To overcome the lack of efficacy of the traditional drugs (and their considerable toxicity), new molecular targets have been studied as starting points to the discovery of new antichagasic compounds. Among them, polyamine transporter TcPAT12 (also known as TcPOT1.1) represents an interesting macromolecule, since polyamines are essential for Trypanosoma cruzi, the parasite that causes the illness, but it cannot synthesize them de novo. In this investigation we report the results of a combined ligand-and structurebased virtual screening for the discovery of new inhibitors of TcPAT12. Initially we filtered out ZINC and Drugbank databases with similarity and QSAR models and then we submitted the candidates to a validated docking based screening. Four structures were selected and tested in T. cruzi epimastigotes proliferation and two of them, Cisapride and [2-(cyclopentyloxy)phenyl]methanamine showed inhibitory effects. Additionally, we performed transport assays which demonstrated that Cisapride interferes with putrescine uptake in a specific mode.

Recent Trends on QSAR in the Pharmaceutical Perceptions, 2012

Journal of Chemical Information and Modeling, Jun 13, 2022

Malaria is a common infectious disease caused by Plasmodium species and the most lethal malarial ... more Malaria is a common infectious disease caused by Plasmodium species and the most lethal malarial parasite is P. falciparum. Considering the high malaria mortality rate and rapid emergence of multi drug resistant strains of malarial parasites necessitates the development of novel drugs. In this work, Adenosine Deaminase (ADA), the first enzyme of the purine salvage pathway was selected as a drug target due to its significant role in nucleic acid biosynthesis. Since the experimental structure of P. falciparum ADA is not available in Protein Data Bank (PDB), the target protein was modeled using comparative homology modeling approach. The overall quality of the model was good in terms of backbone dihedral angles distribution, ERRAT values, Profiles 3D score, knowledge based energy score and Z-score. The physico-chemical properties, secondary elements and active site pockets were analyzed using various in silico tools. Drug-like compounds retrieved from PubChem database was subjected to molecular docking with ADA. Pranlukast, the promising lead identified shows comparatively lower binding free energy compared to the control (5'-Methylthiocoformycin) and interacts with ADA through two hydrogen bonds as well as hydrophobic interactions. The molecular dynamics (MD) simulation studies revealed that Pranlukast binding does not have major alteration in the compactness and mobility of the protein backbone structure but it has an influence in the folding pattern and intramolecular hydrogen bonds formation. Thus, Pranklukast seems to be a potential inhibitor against P. falciparum ADA, which needs further validation by in vitro or in vivo experimental studies.

Communications in Computer and Information Science

Polish Journal of Chemistry, 1999

Chemistry & Biodiversity, Dec 16, 2021

Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation a... more Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation and osmotic regulation of trypanosomatids; in some trypanosomatid species, they have been validated as molecular targets for the development of new therapeutic agents. Because the experimental structure of Trypanosoma cruzi PDEb1 (TcrPDEb1) has not been solved so far, an homology model of the target was created using the structure of Trypanosoma brucei PDEb1 (TbrPDEb1) as a template. The model was refined by extensive enhanced sampling molecular dynamics simulations, and representative snapshots were extracted from the trajectory by combined clustering analysis. This structural ensemble was used to develop a structure‐based docking model of the target. The docking accuracy of the model was validated by redocking and cross‐docking experiments using all available crystal structures of TbrPDEb1, whereas the scoring accuracy was validated through a retrospective screen, using a carefully curated dataset of compounds assayed against TbrPDEb1 and/or TcrPDEb1. Considering the results from in silico validations, the model may be applied in prospective virtual screening campaigns to identify novel hits, as well as to guide the rational design of potent and selective inhibitors targeting this enzyme.

Bioorganic & Medicinal Chemistry, Aug 1, 2007

A series of new xanthone derivatives have been synthesized and evaluated for their anticonvulsant... more A series of new xanthone derivatives have been synthesized and evaluated for their anticonvulsant properties in the maximal electroshock (MES), subcutaneous metrazole (ScMet) tests as well as for neurotoxicity in the rotarod (TOX) in mice, i.p. and rats, p.o. Compound 9: R,S-2-{2-[(1-hydroxybutan-2-yl]amino)ethoxy}-9H-xanthen-9-one and compound 12: R,S-2-{3-[(1-hydroxybutan-2-yl)amino]propoxy}-9H-xanthen-9-one exerted activity in rats, p.o. 2 and 4 h after administration, respectively. Therefore, metabolic stability of the compounds was evaluated with use of rats microsomes, resulting in half-life t 1/2 136 and 108 min, respectively, indicating that either the metabolites are very active, or the parent compounds exert other ADME properties other than metabolism which influence the late onset of activity.

Journal of Enzyme Inhibition and Medicinal Chemistry, 2019

In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide... more In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED 50 ¼ 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).

Journal of Chemical Information and Modeling, May 19, 2010

BENTHAM SCIENCE PUBLISHERS eBooks, Jul 2, 2012

European Journal of Chemistry, Mar 31, 2013

Kinetic study of benzyl sulfamide synthesis by thermolysis of N-(benzyl)-N´-(tert-butoxycarbolyl)... more Kinetic study of benzyl sulfamide synthesis by thermolysis of N-(benzyl)-N´-(tert-butoxycarbolyl) sulfamide

Journal of Chemical Information and Modeling, Jun 27, 2022

Journal of Chemical Information and Modeling, Jul 27, 2021

The scientific community is working against the clock to arrive at therapeutic interventions to t... more The scientific community is working against the clock to arrive at therapeutic interventions to treat patients with COVID-19. Among the strategies for drug discovery, virtual screening approaches have the capacity to search potential hits within millions of chemical structures in days, with the appropriate computing infrastructure. In this article, we first analyzed the published research targeting the inhibition of the main protease (Mpro), one of the most studied targets of SARS-CoV-2, by docking-based methods. An alarming finding was the lack of an adequate validation of the docking protocols (i.e., pose prediction and virtual screening accuracy) before applying them in virtual screening campaigns. The performance of the docking protocols was tested at some level in 57.7% of the 168 investigations analyzed. However, we found only three examples of a complete retrospective analysis of the scoring functions to quantify the virtual screening accuracy of the methods. Moreover, only two publications reported some experimental evaluation of the proposed hits until preparing this manuscript. All of these findings led us to carry out a retrospective performance validation of three different docking protocols, through the analysis of their pose prediction and screening accuracy. Surprisingly, we found that even though all tested docking protocols have a good pose prediction, their screening accuracy is quite limited as they fail to correctly rank a test set of compounds. These results highlight the importance of conducting an adequate validation of the docking protocols before carrying out virtual screening campaigns, and to experimentally confirm the predictions made by the models before drawing bold conclusions. Finally, successful structure-based drug discovery investigations published during the redaction of this manuscript allow us to propose the inclusion of target flexibility and consensus scoring as alternatives to improve the accuracy of the methods.

Frontiers in Pharmacology

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication... more Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Res...

Journal of Computer-Aided Molecular Design

Journal of Chemical Information and Modeling

Polish Journal of Chemistry, 1999

European Journal of Medicinal Chemistry, 2018

Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old dru... more Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old drugs, benznidazole and nifurtimox, which have restricted efficacy against the chronic phase of the illness. To overcome the lack of efficacy of the traditional drugs (and their considerable toxicity), new molecular targets have been studied as starting points to the discovery of new antichagasic compounds. Among them, polyamine transporter TcPAT12 (also known as TcPOT1.1) represents an interesting macromolecule, since polyamines are essential for Trypanosoma cruzi, the parasite that causes the illness, but it cannot synthesize them de novo. In this investigation we report the results of a combined ligand-and structurebased virtual screening for the discovery of new inhibitors of TcPAT12. Initially we filtered out ZINC and Drugbank databases with similarity and QSAR models and then we submitted the candidates to a validated docking based screening. Four structures were selected and tested in T. cruzi epimastigotes proliferation and two of them, Cisapride and [2-(cyclopentyloxy)phenyl]methanamine showed inhibitory effects. Additionally, we performed transport assays which demonstrated that Cisapride interferes with putrescine uptake in a specific mode.

Recent Trends on QSAR in the Pharmaceutical Perceptions, 2012

Journal of Chemical Information and Modeling, Jun 13, 2022

Malaria is a common infectious disease caused by Plasmodium species and the most lethal malarial ... more Malaria is a common infectious disease caused by Plasmodium species and the most lethal malarial parasite is P. falciparum. Considering the high malaria mortality rate and rapid emergence of multi drug resistant strains of malarial parasites necessitates the development of novel drugs. In this work, Adenosine Deaminase (ADA), the first enzyme of the purine salvage pathway was selected as a drug target due to its significant role in nucleic acid biosynthesis. Since the experimental structure of P. falciparum ADA is not available in Protein Data Bank (PDB), the target protein was modeled using comparative homology modeling approach. The overall quality of the model was good in terms of backbone dihedral angles distribution, ERRAT values, Profiles 3D score, knowledge based energy score and Z-score. The physico-chemical properties, secondary elements and active site pockets were analyzed using various in silico tools. Drug-like compounds retrieved from PubChem database was subjected to molecular docking with ADA. Pranlukast, the promising lead identified shows comparatively lower binding free energy compared to the control (5'-Methylthiocoformycin) and interacts with ADA through two hydrogen bonds as well as hydrophobic interactions. The molecular dynamics (MD) simulation studies revealed that Pranlukast binding does not have major alteration in the compactness and mobility of the protein backbone structure but it has an influence in the folding pattern and intramolecular hydrogen bonds formation. Thus, Pranklukast seems to be a potential inhibitor against P. falciparum ADA, which needs further validation by in vitro or in vivo experimental studies.

Communications in Computer and Information Science