Antimalarial Artemisinins Derivatives Study: Molecular Modeling and Multivariate Analysis (PCA, HCA, KNN, SIMCA and SDA)

Macêdo, Williams Jorge da Cruz; Braga, Francinaldo Sarges; Santos, César F.; Costa, Josivan da Silva; Melo, Geraldo Souza de; Mello, Marcello Neiva de; Sousa, Daniele Salgado; Carvalho, José Carlos Tavares; Socorro, Davi do; Brasil, Davi do Socorro Barros; Santos, Cleydson Breno Rodrigues dos

doi:10.1166/jctn.2015.4138

Cited by 10 publications

(16 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, the frequencies were also calculated using B3LYP/6-31+G(d,p) and observed that there were no negative frequencies, thereby ensuring that local minimum energy structure [60]. The phenylbutazone derivatives and therapeutic targets structures for molecular docking study were prepared using the software Discovery Studio 5.0 (San Diego, CA, USA) [61], removing the water molecules and for docking validations were downloaded with the therapeutic targets crystal structures and crystallographic inhibitors were used in molecular docking study, as well as, in validation through of the root-mean-square deviation (RMSD) value between the experimental data with computational data, according to studies carried out by Macêdo et al (2015) [62] and Federico et al (2017) [63].…”

Section: Methodsmentioning

confidence: 99%

Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

et al. 2019

View full text Add to dashboard Cite

A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13–15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13–15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.

show abstract

Section: Methodsmentioning

confidence: 99%

Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

et al. 2019

View full text Add to dashboard Cite

show abstract

“…According to literature, the binding mode prediction using docking should present root mean square deviation (RMSD) value <2.0 Å when superimposed to the crystallographic pose of the ligand [46][47][48]. So, the search parameters were suitable for the docking step and the accuracy of the docking study was corroborated/validated by the crystallographic pose of the agonist into the A 2A AR active site, reinforcing the reliability of our computational protocol to search for new potential leads or hits [23,30].…”

Section: Molecular Docking Studiesmentioning

confidence: 64%

“…According to the statistical quality (regression parameters), the best model constructed is shown in Equation 3 [29], the F value is found to be statistically significant at 95.00% level, since the entire value of F calculated is higher when compared to tabulated values. By Costa [30], a higher F value implies a more significant correlation was achieved. This combination of molar volume (MV), molar polarizability (MP), number of atoms (NA), pharmacophore features (PF), and hydrophobic group (HG) showed relevant statistics (r = 0.9634) and explained up to 89.22% of the variance of r 2 A .…”

Section: Pentaparametric Modelsmentioning

confidence: 99%

“…The objective of autoescale was to give each descriptor equal weight in mathematical terms and each variable was centered on the average, being scaled to unit variance. As the biological data of EC 50 (nM) were obtained from different sources, the EC 50 values were converted to pEC 50 = −logEC 50 , in order to reduce the inconsistencies caused by experimental steps [30].…”

Section: Correlation Analysis Design and Validation Of The Multiple mentioning

confidence: 99%

See 1 more Smart Citation

Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

et al. 2020

View full text Add to dashboard Cite

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.

show abstract

“…After selection it was necessary to optimize the structures, since the use of conformations that are not bioactive or pharmacophoric conformations, in conformationally flexible molecules can lead to errors in the interaction models and to solve the problem the structures were redesigned and optimized in the program HyperChem 7.1 [22,23]. The method selected was Molecular Mechanics with the MM + force field [24], which is faster and simpler than the semi-empirical method because the structures in question being polypeptides, have relatively large sizes and thus require time and increase the number of computational cycles required to calculate the energy of the molecule [25]. Molecular mechanics (MM) calculations are force field calculations using gradient lowering methods for geometry optimization, which generally leads to more stable conformation, but not of the least energy.…”

Section: Resultsmentioning

confidence: 99%

Identification of New Inhibitors with Potential Antitumor Activity from Polypeptide Structures via Hierarchical Virtual Screening

et al. 2019

View full text Add to dashboard Cite

Leukemias are neoplasms that affect hematopoietic cells, which are developed by genetic alterations (mutations) that lead to the loss of proliferation control mechanisms (maturation and/or cell death). The α4β1 integrin receptor is a therapeutic target for inflammation, autoimmune diseases and lymphoid tumors. This study was carried out to search through the antagonists-based virtual screening for α4β1 receptor. Initially, seventeen (17) structures were selected (based on the inhibitory activity values, IC50) and the structure with the best value was chosen as the pivot. The pharmacophoric pattern was determined from the online PharmaGist server and resulted in a model of score value equal to 97.940 with 15 pharmacophoric characteristics that were statistically evaluated via Pearson correlations, principal component analysis (PCA) and hierarchical clustering analysis (HCA). A refined model generated four pharmacophoric hypotheses totaling 1.478 structures set of Zinc_database. After, the pharmacokinetic, toxicological and biological activity predictions were realized comparing with pivot structure that resulted in five (ZINC72088291, ZINC68842860, ZINC14365931, ZINC09588345 and ZINC91247798) structures with optimal in silico predictions. Therefore, future studies are needed to confirm antitumor potential activity of molecules selected this work with in vitro and in vivo assays.

show abstract

Antimalarial Artemisinins Derivatives Study: Molecular Modeling and Multivariate Analysis (PCA, HCA, KNN, SIMCA and SDA)

Cited by 10 publications

References 0 publications

Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

Identification of New Inhibitors with Potential Antitumor Activity from Polypeptide Structures via Hierarchical Virtual Screening

Contact Info

Product

Resources

About