A study of new antimalarial artemisinins through molecular modeling and multivariate analysis

Ferreira, João Elias Vidueira; Figueiredo, Antonio Florêncio de; Barbosa, Jardel Pinto; Cristino, Maria G. G.; Macêdo, Williams Jorge da Cruz; Silva, Osmarina P. P.; Malheiros, Bruno V.; Serra, Raymony Tayllon Alves; Ciríaco-Pinheiro, José

doi:10.2298/jsc100126124f

Cited by 11 publications

(15 citation statements)

References 29 publications

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“…This is in agreement with recent literature theoretical findings,25 where it has been suggested that an electrophilic attack of the heme Fe 2+ could occur through the involvement of the endoperoxide linkage. The main in‐crystal Φ ( r ) MM‐EXP minimum amounts to −143(19) kcal mol −1 and is closer to the O4 (1.432 Å from the minimum) than to the O3 atom (1.531 Å).…”

Section: Resultssupporting

confidence: 93%

Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

Saleh

Soave

Presti

et al. 2013

Chemistry A European J

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The accurate, experimental charge density distribution, ρ(r), of the potent antimalarial drug dihydroartemisinin (DHA) has been derived for the first time from single-crystal X-ray diffraction data at T=100(2) K. Gas-phase and solid-state DFT simulations have also been performed to provide a firm basis of comparison with experimental results. The quantum theory of atoms in molecules (QTAIM) has been employed to analyse the ρ(r) scalar field, with the aim of classifying and quantifying the key real-space elements responsible for the known pharmacophoric features of DHA. From the conformational perspective, the bicyclo[3.2.2]nonane system fixes the three-dimensional arrangement of the 1,2,4-trioxane bearing the active O-O redox centre. This is the most nucleophilic function in DHA and acts as an important CH⋅⋅⋅O acceptor. On the contrary, the rest of the molecular backbone is almost neutral, in accordance with the lipophilic character of the compound. Another remarkable feature is the C-O bond length alternation along the O-C-O-C polyether chain, due to correlations between pairs of adjacent C-O bonds. These bonding features have been related with possible reactivity routes of the α- and β-DHA epimers, namely 1) the base-catalysed hemiacetal breakdown and 2) the peroxide reduction. As a general conclusion, the base-driven proton transfer has significant non-local effects on the whole polyether chain, whereas DHA reduction is thermodynamically favourable and invariably leads to a significant weakening (or even breaking) of the O-O bond. The influence of the hemiacetal stereochemistry on the electronic properties of the system has also been considered. Such findings are discussed in the context of the known chemical reactivity of this class of important antimalarial drugs.

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Section: Resultssupporting

confidence: 93%

Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

Saleh

Soave

Presti

et al. 2013

Chemistry A European J

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“…A comparison of the reported QSAR models on the artemisinin analogues [53][54][55][56][57] and the GRNN model developed in this work is given in ▶ table 4. Although, the calculated descriptors were not similar in the reported works, this comparison reveals the ability of GRNN to predict the activity of artemisinin analogues.…”

Section: Resultsmentioning

confidence: 99%

QSAR Study of Artemisinin Analogues as Antimalarial Drugs by Neural Network and Replacement Method

Abbasitabar

Zare-Shahabadi

2017

Drug Res (Stuttg)

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Quantitative structure-activity relationship (QSAR) models were derived for 179 analogues of artemisinin, a potent antimalarial agent. Molecular descriptors derived solely from molecular structure were used to represent molecular structure. Utilizing replacement method, a subset of 11 descriptors was selected. General regression neural network (GRNN) was used to construct the nonlinear QSAR models in all stages of study. The relative standard error percent in antimalarial activity predictions for the training set by the application of cross-validation (RMSE-CV) was 0.43, and for test set (RMSE) was 0.51. GRNN analysis yielded predicted activities in the excellent agreement with the experimentally obtained values (R2training = 0.967 and R2test = 0.918). The mean absolute error for the test set was computed as 0.4115.

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“…This information is transformed and encoded for lots of problems chemical, pharmacological and toxicological studies on the relationship between structure-activity, quantitative structure-activity and structure-property (SAR, QSAR and QSPR) [79]- [81]. Ferreira et al [82] studied artemisinin and 18 derivatives with antimalarial activity against W-2 strains of Plasmodium falciparum through quantum chemistry and multivariate analysis. The geometry optimization of structures was realized using the Hartree-Fock method and the 3-21G** basis set.…”

Section: Application Of Hartree-fock Methods Using Computational Toolsmentioning

confidence: 99%

Application of Hartree-Fock Method for Modeling of Bioactive Molecules Using SAR and QSPR

Santos¹,

Lobato²,

Braga³

et al. 2014

CMB

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The central importance of quantum chemistry is to obtain solutions of the Schrödinger equation for the accurate determination of the properties of atomic and molecular systems that occurred from the calculation of wave functions accurate for many diatomic and polyatomic molecules, using Self Consistent Field method (SCF). The application of quantum chemical methods in the study and planning of bioactive compounds has become a common practice nowadays. From the point of view of planning it is important to note, when it comes to the use of molecular modeling, a collective term that refers to methods and theoretical modeling and computational techniques to mimic the behavior of molecules, not intend to reach a bioactive molecule simply through the use of computer programs. The choice of method for energy minimization depends on factors related to the size of the molecule, parameters of availability, stored data and computational resources. Molecular models generated by the computer are the result of mathematical equations that estimate the positions and properties of the electrons and nuclei, the calculations exploit experimentally, the characteristics of a structure, providing a new perspective on the molecule. In this work we show that studies of

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A study of new antimalarial artemisinins through molecular modeling and multivariate analysis

Cited by 11 publications

References 29 publications

Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

QSAR Study of Artemisinin Analogues as Antimalarial Drugs by Neural Network and Replacement Method

Application of Hartree-Fock Method for Modeling of Bioactive Molecules Using SAR and QSPR

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