Identification of Potential Antiviral Inhibitors from Hydroxychloroquine and 1,2,4,5-Tetraoxanes Analogues and Investigation of the Mechanism of Action in SARS-CoV-2

Ramos, Ryan da Silva; Borges, Rosivaldo S.; Souza, João Sammy Nery de; Araújo, Inana F.; Chaves, Mariana Helena; Santos, Cleydson Breno Rodrigues dos

doi:10.3390/ijms23031781

Cited by 15 publications

(13 citation statements)

References 69 publications

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“…The LogP parameter affects the ability of a molecule to decompose in non-polar versus aqueous environments [ 44 ]. GNT showed the highest consensual LogPo/w with a value of 3.33 (see Table 13 ), low solubility in water, and requiring organic solvents for solubilization.…”

Section: Resultsmentioning

confidence: 99%

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach

et al. 2023

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Acetylcholinesterase (AChE) enzymes play an essential role in the development of Alzheimer’s disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the hAChE B site of the human acetylcholinesterase (hAChE) enzyme employed in this investigation, which was obtained from the Protein Data Bank (PDB ID 4EY6), allowed for the prediction of the binding affinity and free binding energy between the protein and the ligand. Virtual screening was performed to obtain structures similar to Galantamine (GNT) with potential hAChE activity. The top 200 hit compounds were prioritized through the use of filters in ZincPharmer, with special features related to the pharmacophore. Critical analyses were carried out, such as hierarchical clustering analysis (HCA), ADME/Tox predictions, molecular docking, molecular simulation studies, synthetic accessibility (SA), lipophilicity, water solubility, and hot spots to confirm the stable binding of the two promising molecules (ZINC16951574-LMQC2, and ZINC08342556-LMQC5). The metabolism prediction, with metabolites M3-2, which is formed by Glutathionation reaction (Phase II), M1-2, and M2-2 formed from the reaction of S-oxidation and Aliphatic hydroxylation (Phase I), were both reactive but with no side effects. Theoretical synthetic routes and prediction of synthetic accessibility for the most promising compounds are also proposed. In conclusion, this study shows that in silico modeling can be used to create new drug candidate inhibitors for hAChE. The compounds ZINC16951574-LMQC2, and ZINC08342556-LMQC5 are particularly promising for oral administration because they have a favorable drug-likeness profile, excellent lipid solubility, high bioavailability, and adequate pharmacokinetics.

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Section: Resultsmentioning

confidence: 99%

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach

et al. 2023

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“…The selected compounds M01 – M05 , after hierarchical virtual screening, were submitted for evaluation of synthetic accessibility ( Table 5 ); all five compounds were easily synthesized, with scores above 89 [ 145 , 146 , 147 ]. According to classification by score, the value of 100 is the maximum synthetic accessibility; that is, the molecule is more easily synthesized if it has a higher score (see Table 5 ).…”

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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“…However, 2 promising compounds (PC-53093220 and PC-53116405) did not show predicted biological or cytotoxic activity (Pa > Pi). This fact should not be seen as a lack of activity, since even compounds with known and potent activity can present a low value of Pa or even Pa < Pi during the prediction ( Ramos et al, 2022 ; Lagunin et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Hierarchical Virtual Screening Based on Rocaglamide Derivatives to Discover New Potential Anti-Skin Cancer Agents

Santos

Borges

Silva

et al. 2022

Front. Mol. Biosci.

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Skin Cancer (SC) is among the most common type of cancers worldwide. The search for SC therapeutics using molecular modeling strategies as well as considering natural plant-derived products seems to be a promising strategy. The phytochemical Rocaglamide A (Roc-A) and its derivatives rise as an interesting set of reference compounds due to their in vitro cytotoxic activity with SC cell lines. In view of this, we performed a hierarchical virtual screening study considering Roc-A and its derivatives, with the aim to find new chemical entities with potential activity against SC. For this, we selected 15 molecules (Roc-A and 14 derivatives) and initially used them in docking studies to predict their interactions with Checkpoint kinase 1 (Chk1) as a target for SC. This allowed us to compile and use them as a training set to build robust pharmacophore models, validated by Pearson’s correlation (p) values and hierarchical cluster analysis (HCA), subsequentially submitted to prospective virtual screening using the Molport® database. Outputted compounds were then selected considering their similarities to Roc-A, followed by analyses of predicted toxicity and pharmacokinetic properties as well as of consensus molecular docking using three software. 10 promising compounds were selected and analyzed in terms of their properties and structural features and, also, considering their previous reports in literature. In this way, the 10 promising virtual hits found in this work may represent potential anti-SC agents and further investigations concerning their biological tests shall be conducted.

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Identification of Potential Antiviral Inhibitors from Hydroxychloroquine and 1,2,4,5-Tetraoxanes Analogues and Investigation of the Mechanism of Action in SARS-CoV-2

Cited by 15 publications

References 69 publications

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach

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

Hierarchical Virtual Screening Based on Rocaglamide Derivatives to Discover New Potential Anti-Skin Cancer Agents

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