Chemometric methods in antimalarial drug design from 1,2,4,5-tetraoxanes analogues

Costa, Edson B.; Silva, R.C.; Espejo-Román, José M.; Neto, Moysés Fagundes de Araújo; Cruz, Jorddy Neves; Leite, Franco Henrique Andrade; Silva, C.H.T.P.; Pinheiro, José; Macêdo, Williams Jorge da Cruz; Santos, Cleydson Breno Rodrigues dos

doi:10.1080/1062936x.2020.1803961

Cited by 44 publications

(23 citation statements)

References 53 publications

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“…The studies of molecular dynamics simulations were carried out to understand more deeply the modes of interaction of the selected compounds with the target proteins. The results obtained through molecular dynamics simulations have served as support for the detailed evaluation of conformations over time observed in drug-receptor complexes [39][40][41]. Thus, understanding that the dynamics and changes in the movement of a protein are closely related to its biological function allows us to understand that the observation of these phenomena is extremely important.…”

Section: Molecular Dynamics Results and Affinity Energymentioning

confidence: 80%

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

et al. 2020

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Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side effects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson’s correlation for the construction of quantitative structure–activity relationship (QSAR) models to predict the biological activities of the compounds obtained with virtual screening. The pharmacokinetic/toxicological profiles of the compounds were determined, as well as the binding modes through molecular docking compared to commercial compounds (rofecoxib and celecoxib). The QSAR analysis showed a fit with R = 0.9617, R2 = 0.9250, standard error of estimate (SEE) = 0.2238, and F = 46.2739, with the tetra-parametric regression model. After the analysis, only three promising inhibitors were selected, Z-964, Z-627, and Z-814, with their predicted pIC50 (−log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski’s rule of five, which predicts a good oral availability and can be used in in vitro and in vivo tests in the zebrafish model in order to confirm the obtained in silico data.

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Section: Molecular Dynamics Results and Affinity Energymentioning

confidence: 80%

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

et al. 2020

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“…The evaluation of the obtained complexes was carried out using the root-mean-square deviation RMSD between the ligands. According to the literature, for the docking protocol to be validated, the RMSD between the redocked and the crystallographic ligand must be less than 2 Å [ 59 , 60 , 61 , 62 ]. In our results, an RMSD of 1.42 Å was obtained.…”

Section: Resultsmentioning

confidence: 99%

Chemical Composition and Preliminary Toxicity Evaluation of the Essential Oil from Peperomia circinnata Link var. circinnata. (Piperaceae) in Artemia salina Leach

et al. 2021

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Peperomia Ruiz and Pav, the second largest genus of the Piperaceae, has over the years shown potential biological activities. In this sense, the present work aimed to carry out a seasonal and circadian study on the chemical composition of Peperomia circinata essential oils and aromas, as well as to evaluate the preliminary toxicity in Artemia salina Leach and carry out an in silico study on the interaction mechanism. The chemical composition was characterized by gas chromatography (GC/MS and GC-FID). In the seasonal study the essential oil yields had a variation of 1.2–7.9%, and in the circadian study the variation was 1.5–5.6%. The major compounds in the seasonal study were β-phellandrene and elemicin, in the circadian they were β-phellandrene and myrcene, and the aroma was characterized by the presence of β-phellandrene. The multivariate analysis showed that the period and time of collection influenced the essential oil and aroma chemical composition. The highest toxicity value was observed for the essential oil obtained from the dry material, collected in July with a value of 14.45 ± 0.25 μg·mL−1, the in silico study showed that the major compounds may be related to potential biological activity demonstrated by the present study.

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“…It is worth mentioning that such positive values indicate that all molecules that are highly lipophilic meet an essential criterion for a drug candidate [54]. Initially, hydroxicloquine, chloroquine, and 14 structures of 1,2,4,5 tetraoxane analogues were selected from the literature with proven in vitro testing against malaria caused by Plasmodium falciparum-Sierra Leone clone D-6 to form the training set (Figure S1, see Supplementary Materials), followed by chemometric analysis studies [56]. The molecules were optimized by the computational method DFT B3LYP 6-31G** to obtain bioactive conformation and later used as input files (in .mol and .sdf formats).…”

Section: Prediction Of Lipophilicity and Water Solubility For Promisi...mentioning

confidence: 99%

“…Promising molecules were evaluated with SwissADME software [53,55,56] for the prediction of lipophilicity and water solubility expressed by means of values of logP and logS, respectively. SwissADME provides five methods to predict logP values: iLOGP, xLOGP3, WLOGP, MLOGP, and Silicos-IT.…”

Section: Prediction Of Lipophilicity and Water Solubility For Promisi...mentioning

confidence: 99%

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

Borges

Souza

et al. 2022

IJMS

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This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport® database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood–brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of −8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = −8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.

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Chemometric methods in antimalarial drug design from 1,2,4,5-tetraoxanes analogues

Cited by 44 publications

References 53 publications

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

Chemical Composition and Preliminary Toxicity Evaluation of the Essential Oil from Peperomia circinnata Link var. circinnata. (Piperaceae) in Artemia salina Leach

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

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