Identification of novel antiplasmodial compound by hierarquical virtual screening and<i>in vitro</i>assays

Júnior, David Bacelar Costa; Araújo, Janay Stefany Carneiro; Oliveira, Larissa de Mattos; Neri, Flávio Simas Moreira; Moreira, Paulo Otávio Lourenço; Taranto, Alex Gutterres; Fonseca, Amanda Luisa da; Varotti, Fernando de Pilla; Leite, Franco Henrique Andrade

doi:10.1080/07391102.2020.1763837

Cited by 7 publications

(2 citation statements)

References 40 publications

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“…Among the 4793 compounds prioritized in the virtual pharmacophore-based screening of the Zinc15 database, 4142 compounds (ΔG < 0 kcal/mol) were aligned to the binding site of the crystalline structure of the juvenile hormone protein macromolecules (code PDB: 5V13) of Aedes aegypti ; its complexed binding site has the reference ligand JH3 (methyl (2 E ,6 E )-9-[(2 R )-3,3-dimethyloxiran-2-yl]-3,7-dimethylnona-2,6-dienoate). Therefore, 2240 (LE <−0.40 kcal/mol) compounds were chosen since the efficiency of the ligand selects a more concordant compound for the choice of a principal compound [ 56 , 57 , 58 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Potential Insect Growth Inhibitor against Aedes aegypti: A Bioinformatics Approach

Costa

Neto

Silva

et al. 2022

IJMS

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Aedes aegypti is the main vector that transmits viral diseases such as dengue, hemorrhagic dengue, urban yellow fever, zika, and chikungunya. Worldwide, many cases of dengue have been reported in recent years, showing significant growth. The best way to manage diseases transmitted by Aedes aegypti is to control the vector with insecticides, which have already been shown to be toxic to humans; moreover, insects have developed resistance. Thus, the development of new insecticides is considered an emergency. One way to achieve this goal is to apply computational methods based on ligands and target information. In this study, sixteen compounds with acceptable insecticidal activities, with 100% larvicidal activity at low concentrations (2.0 to 0.001 mg·L−1), were selected from the literature. These compounds were used to build up and validate pharmacophore models. Pharmacophore model 6 (AUC = 0.78; BEDROC = 0.6) was used to filter 4793 compounds from the subset of lead-like compounds from the ZINC database; 4142 compounds (dG < 0 kcal/mol) were then aligned to the active site of the juvenile hormone receptor Aedes aegypti (PDB: 5V13), 2240 compounds (LE < −0.40 kcal/mol) were prioritized for molecular docking from the construction of a chitin deacetylase model of Aedes aegypti by the homology modeling of the Bombyx mori species (PDB: 5ZNT), which aligned 1959 compounds (dG < 0 kcal/mol), and 20 compounds (LE < −0.4 kcal/mol) were predicted for pharmacokinetic and toxicological prediction in silico (Preadmet, SwissADMET, and eMolTox programs). Finally, the theoretical routes of compounds M01, M02, M03, M04, and M05 were proposed. Compounds M01–M05 were selected, showing significant differences in pharmacokinetic and toxicological parameters in relation to positive controls and interaction with catalytic residues among key protein sites reported in the literature. For this reason, the molecules investigated here are dual inhibitors of the enzymes chitin synthase and juvenile hormonal protein from insects and humans, characterizing them as potential insecticides against the Aedes aegypti mosquito.

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Section: Resultsmentioning

confidence: 99%

Identification of Potential Insect Growth Inhibitor against Aedes aegypti: A Bioinformatics Approach

Costa

Neto

Silva

et al. 2022

IJMS

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“…In vitro cytotoxicity of the compounds was assessed against human pulmonary fibroblast cells WI-26VA4 (ATCC CCL-95.1, USA), by 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT assay) [33]. Cells were cultured in a RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum in a 96-well plate.…”

Section: In Vitro Cytotoxicity On Mammalian Cellsmentioning

confidence: 99%

Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria

et al. 2022

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Malaria is an infectious disease widespread in underdeveloped tropical regions. The most severe form of infection is caused by Plasmodium falciparum, which can lead to development of cerebral malaria (CM) and is responsible for deaths and significant neurocognitive sequelae throughout life. In this context and considering the emergence and spread of drug-resistant P. falciparum isolates, the search for new antimalarial candidates becomes urgent. β-carbolines alkaloids are good candidates since a wide range of biological activity for these compounds has been reported. Herein, we designed 20 chemical entities and performed an in silico virtual screening against a pool of P. falciparum molecular targets, the Brazilian Malaria Molecular Targets (BRAMMT). Seven structures showed potential to interact with PfFNR, PfPK7, PfGrx1, and PfATP6, being synthesized and evaluated for in vitro antiplasmodial activity. Among them, compounds 3–6 and 10 inhibited the growth of the W2 strain at µM concentrations, with low cytotoxicity against the human cell line. In silico physicochemical and pharmacokinetic properties were found to be favorable for oral administration. The compound 10 provided the best results against CM, with important values of parasite growth inhibition on the 5th day post-infection for both curative (67.9%) and suppressive (82%) assays. Furthermore, this compound was able to elongate mice survival and protect them against the development of the experimental model of CM (>65%). Compound 10 also induced reduction of the NO level, possibly by interaction with iNOS. Therefore, this alkaloid showed promising activity for the treatment of malaria and was able to prevent the development of experimental cerebral malaria (ECM), probably by reducing NO synthesis.

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Towards development of new antimalarial compounds through in silico and in vitro assays

Junior,

Lacerda,

de Pilla Varotti

et al. 2024

Computational Biology and Chemistry

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Identification of novel antiplasmodial compound by hierarquical virtual screening andin vitroassays

Cited by 7 publications

References 40 publications

Identification of Potential Insect Growth Inhibitor against Aedes aegypti: A Bioinformatics Approach

Identification of Potential Insect Growth Inhibitor against Aedes aegypti: A Bioinformatics Approach

Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria

Towards development of new antimalarial compounds through in silico and in vitro assays

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