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Abstract
ORF8 is an asymmetric-homodimer SARS-COV-2 accessory protein implicated in excesive human inflammation causing numerous deaths. There is no approved drug targeting ORF8, nor it is known whether any anti-ORF8 drugs could reduce human excesive inflammation. Computationally combining ligand co-evolution of parent molecules with affinity-consensus docking, children candidates for docking to ORF8 cavities were generated. Targeting the homodimer interface with the highest affinity children scaffolds, hundreds of grandchildren predicting nanoMolar affinities, unique scaffolds, high specificities and low toxicity risks were generated. Although remaining hypothetical without experimental confirmation, this constitute a new methodological attempt to search for drug-like candidates to interfere with SARS-COV-2-dependent excessive inflammation.
Supplementary materials
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&).
Actions
Title
NTNV.dwam
Description
A DW macro developed to automatically save, label and eliminate children molecules generated during any DW-BEL co-evolution which contained known Toxicity risks (Mutagenesis, Tumorigenicity, Reproductive Interference, Irritant) and/or any of the numerous Nasty Functions (see Nasty_functions.dwar). The NTNV macro uses *.sdf or *.dwar files as inputs, asks for user-renaming 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) (https://www.cdc.gov/niosh/docs/97-119/default.html).
Actions
Title
100top2-grandchildren.dwar
Description
These *.dwar DW tables contain 100 top-grandchildren selected by their ADV affinities from the 2-runs of 16153 . Tables are provided with threshold slider-filters to their DW and ADV docking-scores, Molecular weights and logP properties, to select for particular threshold combinations. The *.dwar files can be opened in DW available at https://openmolecules.org/datawarrior/download.htm
Actions
Title
- 100top2-grandchildren.pse
Description
100 top-grandchildren ADV complexes from the 2-runs of 16153 with the ORF8 asymmetrical homodimer crystalographic 7jtl model to be visualized in PyMol vs2.5.3
Actions
Title
- 100top3-grandchildren.dwar
Description
These *.dwar DW tables contain 100 top-grandchildren selected by their ADV affinities from the 3-runs of 16153. Tables are provided with threshold slider-filters to their DW and ADV docking-scores, Molecular weights and logP properties, to select for particular threshold combinations. The *.dwar files can be opened in DW available at https://openmolecules.org/datawarrior/download.htm.
Actions
Title
- 100top3-grandchildren.pse
Description
100 top-grandchildren ADV complexes from the 3-runs of 16153 with the ORF8 asymmetrical homodimer crystalographic 7jtl model to be visualized in PyMol vs2.5.3.
Actions
