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Abstract
The unique ORF8 is an asymmetric homodimer accessory protein of SARS-COV-2 implicated in pathogenesis by activating excesive human inflammation causing numerous deaths. There is no approved drug targeting ORF8, nor it is known whether any anti-ORF8 drugs could reduce coronavirus-induced excesive inflammation. Computationally combining ligand co-evolution of parent molecules with affinity-ranking by consensus docking, children candidates for ORF8 cavities and ligands were generated. Targeting the interface cavity with the highest affinity children scaffolds, hundreds of grandchildren were generated by specificity-toxicity controlled additional co-evolutions to predict nanoMolar affinities, unique scaffolds, high specificities and low toxicity risks. Although remaining hypothetical without experimental confirmation, these constitute a new methodological attempt to search for drug-like candidates to interfere with SARS-COV-2-dependent excessive inflammation.
Supplementary materials
Title
33top-grandchildren.dwar
Description
These *.dwar DW tables contain 33 top-grandchildren selected by the dw-adv2.py macro for grandchildre predicting < -95 DW docking-scores and - 10 Kcal/mol ADV docking-scores. Tables are provided with threshold slider-filters to their DW and ADV docking-scores, Molecular weights and clogP properties to select particular threshold combinations. The *.dwar files can be opened in DW https://openmolecules.org/datawarrior/download.htm.
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Title
33top-grandchildren.pse
Description
The 33 top-grandchildren ADV complexes with the ORF8 asymmetrical homodimer crystalographic 7jtl model to be visualized in PyMol vs2.5.3. (Figure S3).
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Title
dw-adv2.py
Description
Python macro user-developed to select for the consensus top-children according to user-defined combinations of DW-BEL and ADV docking-score predictions contained in *.sdf files.
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Title
Nasty_functions.dwar
Description
List of previously defined DW Nasty functions of small chemical fragments having known physiological interference problems, kindly supplied by Dr.T.Sander of DW (https://openmolecules.org/forum/ index.php?t=msg&th=662&start=0&).
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Title
NTNV.dwam
Description
. A *.dwam file DW macro developed to save, label and eliminate any children molecules generated during DW-BEL co-evolution which contained any known Toxicity risks (Mutagenesis, Tumorigenicity, Reproductive Interference, Irritant) and/or any of the numerous Nasty Functions (see Nasty_functions.dwar). The macro uses *.sdf or *.dwar files as inputs, user-renamed the input *.dwar file and renamed and saved the corresponding *.sdf file. This saving method supplied *.sdf files maintaining the 3D protein cavity docked to children 3D conformers for visualization in PyMol (using its split_states command) and/or maximal preservation of their 2D geometries for optimal consensus docking (Table S1). More than ~ 3000 traded drugs were taken by DW as low toxicity reference (https://github.com/thsa/datawarrior/blob/master/src/html/ properties/properties.html. Additional information on the DW Toxicity risks evaluated can be found at the Registry of Toxic Effects of Chemical Substances (RTECS data base) (https://www.cdc.gov/niosh/docs/97-119/default.html).
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