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Abstract
To generate high-throughoutput numbers of putative anticoagulant rodenticides, a computational evolutionary method has been applied. In particular, the previously described DataWarrior Build-Evolutionary-Library was optimized to randomly generate made-on-demand brodifacoum-derived children libraries exploring new chemotypes for anticoagulant candidates. The generated children were selected by fitting the brodifacoum-docking cavity of rat-VKORC1 (vitamin K epoxide reductase complex 1) alphafold-modeled using the recent crystallographic human-VKORC1 complex. The non-toxic children predicting the highest affinities (lowest docking-scores) for wild type and resistant rat mutants (Spanish and European) and the lowest affinities for human VKORC1, were consensed by AutoDockVina docking to identify with increased accuracy those anticoagulant candidates predicting rat-VKORC1 nanomolar affinities. The resulting layout library of 150 candidates provided with multi-threshold-adjustable filters, constitute an step forward towards in silico fine-tuning elimination of any other off-target biological species. Chemical synthesis pathway predictions and experimental validations remain to be done
Supplementary materials
Title
Library C containing 150 children with filters in Data Warrior dwar
Description
-150B17+adv.dwar. DW table containing 150 selected putative anticoagulant rodenticide brodifacoum-derived-children. It was provided with threshold slider-filters to their DW docking-scores to VKORC1 (rat, spanish/european mutants, human) and ADV docking-scores to rat VKORC1. The DW table included molecular weights and clogP properties of the putative anticoagulant rodenticides. By up-down moving the slider-filters at the table's right, the best fitting children to particular threshold combinations could be selected. The dwar file can be opened by downloading DataWarrior free access at https://openmolecules.org/datawarrior/download.htm
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Title
Colab notebook for Vina recent vs 1.2.3 docking of pdbqt files prepared in PyRx
Description
-Vina123multi.ipynb. A home-designed Google collaboration notebook (colab web) was employed to confirm PyRx-AutoDockVina docking predictions. The ligands and rat VKORC1 macromolecule pdbqt files and the Vina configuration conf.txt file (including VKORC1 center and docking grid sizes in Angstroms) were prepared for Vina123 docking by the PyRx1.0 (Babel) package, as described before19,20. The ligands (*.pdbqt) and rat VKORC1.pdbqt (macromolecule) files were uploaded to a Google drive and docked with the GPU hardware accelerator
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Title
DataWarrior Macro to label and eliminate toxic molecules generated by Build Evolutionary Library
Description
- toxicprediction.dwam. A DW macro dwam file to label and eliminate toxic children molecules generated by the DW Build Evolutionary Library. The macro uses *.sdf or *.dwar files as inputs, user-renamed the input *.dwar file and renamed and saved the corresponding toxic-free *.dwar and toxic-labeled *.sdf files
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