QSAR analyses of DDT analogues and theirin silicovalidation using molecular docking study against voltage-gated sodium channel ofAnopheles funestus

Abstract

DDT has enjoyed the reputation of a successful pesticide in disease control programme and agricultural practices along with the serious opposition and ban later on due to its biomagnification and toxic action against non-target organisms. The present work was carried out to develop QSAR models for analysing DDT analogues for their pesticidal activity and in silico validation of these models. A 2D-QSAR model was generated using stepwise with multiple regression, and the model with a value of r(2) = 0.7324; q(2) = 0.6215; pred r(2) = 0.7038, containing five descriptors, was selected for further study. The 3D QSAR with CoMFA analysis showed that steric contribution of 21% and electrostatic contribution of about 79% were required for larvicidal activity of DDT analogues. A set of 3430 molecules was generated using the basic DDT skeleton as template, and these were evaluated for their mosquito larvicidal activity using the generated QSAR models and DDT as standard. Eleven molecules were selected for in silico validation of these models. For this, a docking study of the selected molecules against the homology-modelled voltage-gated sodium channel of Anopheles funestus was conducted. The study showed that the activities of these analogues as predicted by 2D-QSAR, 3D-QSAR with CoMFA and dock score were observed to be well correlated.

Recent developments in molecular docking technology applied in food science: a review

“…The production and use of DDT were banned after the 1970s due to its acute toxicity and prolonged presence in the soil. Molecular docking was used to initially validate the QSAR models of DDT, providing a new method for designing high-performance pesticides (Saini & Kumar, 2014). The enzymatic chemistry method commonly used for the rapid detection of pesticides, but the sensitivity of this method is unfortunately not high enough.…”

Z-Matrix template-based substitution approach for enumeration of 3D molecular structures

“…Initial structures (Z-matrix or Cartesian coordinate) are important starting points for the in silico investigation of chemical species. Robust and exhaustive processes to generate chemical structures have been described previously in different contexts [1][2][3][4][5][6][7][8][9]. However, there are still no consistent onesize-fits-all standard for structural enumeration.…”

“…Chemists, by their manual intuition and labour, have been able to identify template structures and substitution points for the combinatorial investigation of compounds. Inspired by the use of this approach in DDT analogues [5], we successfully applied it to 26 classes of compounds to exhaustively generate over ten thousand 3D structures for further investigation by quantum chemical methods [11][12][13][14][15]. Based on these previous reports, this is our first paper devoted to the methodology of generic structure generation using Z-matrix template-based substitution.…”

Z-matrix template-based substitution approach for enumeration of 3D molecular structures

“…Initial structures (Z-matrix or Cartesian coordinate) are important starting points for the in silico investigation of chemical species. Robust and exhaustive processes to generate chemical structures have been described previously in different contexts [1] , [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] . However, there are still no consistent one-size-fits-all standard for structural enumeration.…”

“…The Markush structures, represented as templates with defined substitution points, can be enumerated for the combinatorial investigation of compounds. Inspired by the use of this approach in dichlorodiphenyltrichloroethane (DDT) analogues [5] ( Fig. 1 ), we successfully applied it to 26 classes of compounds to exhaustively generate over ten thousand 3D structures for further investigation by quantum chemical methods [11] , [12] , [13] , [14] , [15] .…”