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QSAR studies on benzothiophene derivatives 20mar20

sex, 20 mar 2020

Publicado por

Authors:

Garcia, Mariana L. 1 ;  de Oliveira, Andrew A. 1 ;  Bueno, V, Renata 1 ;  Nogueira, Victor H. R. 1 ; de Souza, Guilherme E. 1 ; Guido, Rafael V. C. 1


Abstract:

Malaria is an infectious disease caused by protozoan parasites of the genus Plasmodium and transmitted by Anopheles spp. mosquitos. Due to the emerging resistance to currently available drugs, great efforts must be invested in discovering new molecular targets and drugs. N‐myristoyltransferase (NMT) is an essential enzyme to parasites and has been validated as a chemically tractable target for the discovery of new drug candidates against malaria. In this work, 2D and 3D quantitative structure–activity relationship (QSAR) studies were conducted on a series of benzothiophene derivatives as P. falciparum NMT (PfNMT) and human NMT (HsNMT) inhibitors to shed light on the molecular requirements for inhibitor affinity and selectivity. A combination of Quantitative Structure–activity Relationship (QSAR) methods, including the hologram quantitative structure–activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) models, were used, and the impacts of the molecular alignment strategies (maximum common substructure and flexible ligand alignment) and atomic partial charge methods (Gasteiger‐Hückel, MMFF94, AM1‐BCC, CHELPG, and Mulliken) on the quality and reliability of the models were assessed. The best models exhibited internal consistency and could reasonably predict the inhibitory activity against both PfNMT (HQSAR: q2/r2/r2pred = 0.83/0.98/0.81; CoMFA: q2/r2/r2pred = 0.78/0.97/0.86; CoMSIA: q2/r2/r2pred = 0.74/0.95/0.82) and HsNMT (HQSAR: q2/r2/r2pred = 0.79/0.93/0.74; CoMFA: q2/r2/r2pred = 0.82/0.98/0.60; CoMSIA: q2/r2/r2pred = 0.62/0.95/0.56). The results enabled the identification of the polar interactions (electrostatic and hydrogen‐bonding properties) as the major molecular features that affected the inhibitory activity and selectivity. These findings should be useful for the design of PfNMT inhibitors with high affinities and selectivities as antimalarial lead candidates.


1   Sao Carlos Institute of Physics, University of Sao Paulo, Sao Carlos, Sao Paulo, Brazil


Link to article:   https://onlinelibrary.wiley.com/doi/full/10.1002/ddr.21646

 

Espinheira santa 20mar20

sex, 20 mar 2020

Publicado por

Authors:

Bicalho, Keylla U. 1, 2, 3, 4 ; Santoni, Mariana M. 3, 4 ; Arendt, Philipp 1, 2 ; Zanelli, Cleslei F. 4 ; Furlan, Maysa 3 ; Goossens, Alain 1, 2 ; Pollier, Jacob 1, 2, 5


Abstract:

The native Brazilian plant Maytenus ilicifolia accumulates a set of quinone methide triterpenoids with important pharmacological properties, of which maytenin, pristimerin and celastrol accumulate exclusively in the root bark of this medicinal plant. The first committed step in the quinone methide triterpenoid biosynthesis is the cyclization of 2,3-oxidosqualene to friedelin, catalyzed by the oxidosqualene cyclase friedelin synthase (FRS). In this study, we produced heterologous friedelin by the expression of M. ilicifolia FRS in Nicotiana benthamiana leaves and in a Saccharomyces cerevisiae strain engineered using CRISPR/Cas9. Furthermore, friedelin-producing N. benthamiana leaves and S. cerevisiae cells were used for the characterization of CYP712K4, a cytochrome P450 from M. ilicifolia that catalyzes the oxidation of friedelin at the C-29 position, leading to maytenoic acid, an intermediate of the quinone methide triterpenoid biosynthesis pathway. Maytenoic acid produced in N. benthamiana leaves was purified and its structure was confirmed using high-resolution mass spectrometry and nuclear magnetic resonance analysis. The three-step oxidation of friedelin to maytenoic acid by CYP712K4 can be considered as the second step of the quinone methide triterpenoid biosynthesis pathway, and may form the basis for further discovery of the pathway and heterologous production of friedelanes and ultimately quinone methide triterpenoids.


1   Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Ghent, Belgium

2   VIB Center for Plant Systems Biology, 9052 Ghent, Belgium

3   Department of Organic Chemistry, Institute of Chemistry, Sao Paulo State University (UNESP), Araraquara, Sao Paulo, Brazil

4   Department of Biological Sciences, School of Pharmaceutical Sciences, Sao Paulo State University (UNESP), Araraquara, Sao Paulo, Brazil

5   VIB Metabolomics Core, 9052 Ghent, Belgium


 

Link to article:   https://academic.oup.com/pcp/article/60/11/2510/5539493