Exploring non-toxic co-evolutionary docking

Abstract

Drug-spaces of nine crystallographic protein / ligand models have been comparatively explored by including Toxicity Risk assessment during computational co-evolution. Tens of thousands children were randomly generated from parent ligands and iteratively selected for higher affinities, increased specificities and low Toxicity Risk using DataWarrior / Build Evolutionary Library algorithms, mimicking natural evolution. Only a few hours of co-evolution increased ~ 2-fold the numbers of non-toxic children. Top-leads predicted drug-like properties, nanoMolar affinities (confirmed by AutoDockVina), higher specificities, absence of known toxicities, and similar docking to their initial binding cavities. Tables were provided with multi-threshold-adjustable filters for alternative in silico explorations of this new "co-evolutionary docking" tool.

Ligands docking to ORF8 by co-evolution. Could they reduce the inflammation levels induced by SARS-COV-2 infections?

“…Starting DataWarrior "Build Evolutionary Library" with a home-designed parent molecular pseudoligand The DataWarrior (DW) updated program was downloaded (https://openmolecules.org/datawarrior/download.html) following the details for Windows as described before 46,48 .…”

“…The high computer memories required to perform such co-evolutionary searches was higher than in our previously reported work [2][3][4][5] indicating that targeting the ORF8 interface cavities had enormous steric difficulties most probably due to the strong interdigitating amino acids of its monomer faces. The generation of children molecules during coevolution were controlled for molecular weight, hydrophobicity 6,7,[8][9][10][11] and toxicity risks to avoid unspecificities and/or toxic molecules 46 . The most accurate AutoDockVina (ADV) program quantitatively estimated their affinities, and explore for the possibilities of whole ORF8 wide docking cavities 47 .…”

Star-shaped conformers generated by co-evolutionary docking predict cross-fitting glycoprotein trimer pre-fusion interfaces on VHSV fish rhabdovirus

“…The ADV algorithm was selected among the numerous alternative docking programs because of higher accuracies and ongoing improvements 27,28,36,37 . The PyRx/Obabel/ADV algorithms were adapted to large scale docking requirements 38,39 . Previous to ADV docking, non-toxic fitted-children DWBEL-conformers were minimized using the mmff94s+ force-field to conserve their 2D-structures.…”

Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities

“…The DataWarrior-Build Evolutionary Library (DW-BEL) algorithms were employed to generate tens of thousands of raw unique children from one parent molecule and select those fitting an initial protein-ligand cavity (fittedchildren). The Java's DW program was updated for Windows as described before (Table S1) 34,35 including some modifications to adapt to large number of runs. The initial parent molecules were selected from previously proposed KcsA ligands such as quaternary-ammonium compounds (qac) 14 , diacyl-glycerol (dga) 9 or user-designed pseudoligands.…”