Computational Modeling of Antimalarial 10-Substituted Deoxoartemisinins

Cristino, Maria da Glória Gomes; Meneses, Carla Carolina Ferreira; Soeiro, Malúcia Marques; Ferreira, João Elias Vidueira; Figueiredo, Antonio Florêncio de; Barbosa, Jardel Pinto; Almeida, Ruth C. O. De; Pinheiro, José; Pinheiro, Andreia de Lourdes Ribeiro

doi:10.1142/s0219633612500162

Cited by 8 publications

(5 citation statements)

References 44 publications

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“…They used chemometric modeling to reduce dimensionality and determine which subset of descriptors are responsible for the classification between more active (MA) and less active (LA) artemisinins. A predictive study was performed with a new set of eight artemisinins using chemometric methods, and five of them were predicted to be active against D-6 strains of falciparum malaria [25].…”

Section: Introductionmentioning

confidence: 99%

A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

García‐García

Besnard²,

Baux³

et al. 2013

Molecules

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BackgroundUsher syndrome type 2 (USH2) is an autosomal recessive disease characterized by moderate to severe hearing loss and retinitis pigmentosa. To date, three disease-causing genes have been identified, USH2A, GPR98, and DFNB31, of which USH2A is clearly the major contributor. The aim of this work was to determine the contribution of GPR98 and DFNB31 genes in a Spanish cohort of USH2A negative patients using exhaustive molecular analysis, including sequencing, dosage, and splicing analysis.MethodsLinkage analysis was performed to prioritize the gene to study, followed by sequencing of exons and intron-exon boundaries of the selected gene, GPR98 (90 exons) or DFNB31 (12 exons). Functional splicing analyses and comparative genomic hybridization array to detect large rearrangements were performed when appropriate.ResultsWe confirmed that mutations in GPR98 contribute a significant but minor role to Usher syndrome type 2. In a group of patients referred for molecular diagnosis, 43 had been found to be positive for USH2A mutations, the remaining 19 without USH2A alterations were screened, and seven different mutations were identified in the GPR98 gene in seven patients (five in the homozygous state), of which six were novel. All detected mutations result in a truncated protein; deleterious missense mutations were not found. No pathological mutations were identified in the DFNB31 gene.ConclusionsIn Spain, USH2A and GPR98 are responsible for 95.8% and 5.2% of USH2 mutated cases, respectively. DFNB31 plays a minor role in the Spanish population. There was a group of patients in whom no mutation was found. These findings confirm the importance of including at least GPR98 analysis for comprehensive USH2 molecular diagnosis.

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Section: Introductionmentioning

confidence: 99%

A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

García‐García

Besnard²,

Baux³

et al. 2013

Molecules

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“…Applications of MEP to investigate the key features of compounds that are necessary for their biological activities and thus proposing new derivatives as well as the construction of chemometric models as indicative of the most promising among the new derivatives for syntheses and biological assays were reported by us in literature [37][38][39][40][41][42][43]. Pinheiro…”

Section: Mep and Chemometrics Techniques As Tools For The Design Of Bmentioning

confidence: 99%

Molecular Electrostatic Potential and Chemometric Techniques as Tools to Design Bioactive Compounds

Santos¹,

Oliveira²,

Figueiredo³

et al. 2020

Cheminformatics and Its Applications

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In this chapter, firstly, we briefly review aspects of the approximation of quantum chemistry, molecular electrostatic potential (MEP), and chemometrics techniques, which are accredited as important tools in the development of chemical science and are frequently used in the study and design of bioactive compounds. Ultimately, we use MEP and pattern recognition (PR) techniques as tools to design nitrofuran compounds with biological activity against Trypanosoma cruzi (T. cruzi). PR models (PCA, HCA, KNN, SDA, and SIMCA) were constructed and demonstrated that 23 nitrofurans can be classified into two classes or groups: more active and less active according to their degrees of activity against T. cruzi. Properties such as charge on the N atom of the nitro group (QN1); the difference between the highest occupied molecular orbital (HOMO) energy and the lowest unoccupied molecular orbital (LUMO) energy (GAP energy); molecular representation of structure based on electron diffraction code of signal 5, unweighted (Mor05u); and Moriguchi water-octanol partition coefficient (MlogP) are responsible for the classification into more active and less active studied nitrofurans. It is interesting to notice that these properties represent three distinct classes of interactions between the nitrofurans and the biological receptor: electronic (QN1 and GAP energy), steric (Mor05u), and hydrophobic (MlogP). The results of the application of PR models on the validation set evidenced two nitrofuran compounds (compounds 25 and 30) as more promising for synthesis and biological assays, which in the future can be used to validate our PR models.

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“…Cristino et al [36] used the B3LYP/6-31G* method to model artemisinin and 19 10-substituted deoxoartemisinin derivatives, with different degrees of activity against the Plasmodium falciparum D-6 strains of Sierra Leone. Chemometric methods (PCA, HCA, KNN, SIMCA, and SDA) were employed to reduce the dimensionality and to determine which subset of descriptors is responsible for the classification between more and less active agents.…”

Section: Determination Of the Theoretical Geometrical Parameters For mentioning

confidence: 99%

A QSAR, Pharmacokinetic and Toxicological Study of New Artemisinin Compounds with Anticancer Activity

et al. 2014

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Abstract:The Density Functional Theory (DFT) method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with different degrees of cytotoxicity against the human hepatocellular carcinoma HepG2 line. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to select the most important descriptors related to anticancer activity. The significant molecular descriptors related to the compounds with anticancer activity were the ALOGPS_log, Mor29m, IC5 and GAP energy. The Pearson correlation between OPEN ACCESSMolecules 2014, 19 10671 activity and most important descriptors were used for the regression partial least squares (PLS) and principal component regression (PCR) models built. The regression PLS and PCR were very close, with variation between PLS and PCR of R 2 = ±0.0106, R 2 ajust = ±0.0125, s = ±0.0234, F (4,11) = ±12.7802, Q 2 = ±0.0088, SEV = ±0.0132, PRESS = ±0.4808 and S PRESS = ±0.0057. These models were used to predict the anticancer activity of eight new artemisinin compounds (test set) with unknown activity, and for these new compounds were predicted pharmacokinetic properties: human intestinal absorption (HIA), cellular permeability (P CaCO2 ), cell permeability Maden Darby Canine Kidney (P MDCK ), skin permeability (P Skin ), plasma protein binding (PPB) and penetration of the blood-brain barrier (C Brain/Blood ), and toxicological: mutagenicity and carcinogenicity. The test set showed for two new artemisinin compounds satisfactory results for anticancer activity and pharmacokinetic and toxicological properties. Consequently, further studies need be done to evaluate the different proposals as well as their actions, toxicity, and potential use for treatment of cancers.

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Computational Modeling of Antimalarial 10-Substituted Deoxoartemisinins

Cited by 8 publications

References 44 publications

A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

Molecular Electrostatic Potential and Chemometric Techniques as Tools to Design Bioactive Compounds

A QSAR, Pharmacokinetic and Toxicological Study of New Artemisinin Compounds with Anticancer Activity

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