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Abstract
Because of the emergence of F13L mutations in MonkeyPox Virus (MPXV)-infected patients with resistances to Tecovirimat-treatment, alternative drugs are actively searched. Aiming to help on these searches, computational strategies to generate rather than screen for new drug-like ligand candidates were explored here. Ligands were predicted by i) thousands of Tecovirimat-derived children generated by co-evolution fitting predicted docking cavities at either F13L1 or F13L2, and ii) docking Tecovirimat-derived top-children to F13L-mutant resistant models isolated from Tecovirimat-treated patients. Top-children-fitting F13L-mutant docking-cavities predicted novel scaffolds, nanoMolar affinities, high specificities, absence of known toxicities and similar conservation of their targeted Tecovirimat-docking cavities. Despite their limitations, similar proved-on-concept strategies might be fine-tuned to computational explore for new drugs docking to most prevalent Tecovirimat-resistance mutations.
Supplementary materials
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GraphycalAbstract.pse.
Description
Tecovirimat-docked to Alphafold modeled F13Ls (from Figure 2). Tecovirimat was ADV blind-docked to F13L-1 (2003 reference strain), F13L0 (353K mutation of the 2022 clade), and Tecovirimat-resistant pooled single mutations F13L1 and F13L2 coding for most abundant 2022 mutations. Gray cartoons, PyMol merged F13L-1, F13L0, F13L1 and F13L2 Alphafold modeled amino acid carbon alpha backbones. Yellow sticks, Tecovirimat-docked to F13L-1 and to F13L0. Green sticks. Tecovirimat-docked to F13L1. Red sticks, Tecovirimat-docked to F13L2. Green sticks down, F13L 185CC palmytoil sites. Black mesh, F13L 1Met amino terminal.
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1769F13L1.sdf
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1769F13L1.sdf. Data from the 1769 Tecovirimat-derived non-toxic fitted-children (Figure 3, F13L1). The file contains conformer DWBEL generated order (ID), with their corresponding 3D chemical structures, molecular weights, cLogP hydrophobicities, unitless DWBEL docking-scores and kcal/mol ADV affinities. The file can be opened in freely-available either MolSoft (https://www.molsoft.com/download.html) or DW (https://openmolecules.org/datawarrior/download.htm).
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3532F13L2.sdf
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3532F13L2.sdf. Data from the 3532 Tecovirimat-derived non-toxic fitted-children (Figure 3, F13L2). The file contains conformer DWBEL generated order (ID), with their corresponding 3D chemical structures, molecular weights, cLogP hydrophobicities, unitless DWBEL docking-scores and kcal/mol ADV affinities. The file can be opened in freely-available either MolSoft (https://www.molsoft.com/download.html) or DW (https://openmolecules.org/datawarrior/download.htm).
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32F13L1.sdf
Description
32F13L1.sdf. Data from 32 Tecovirimat-derived non-toxic fitted-top-children consensus of < -85 DWBEL and < -11 kcal/mol ADV (Figure 3 F13L1 and 1769F13L1.sdf). The file contains generated conformer DWBEL order (ID), with their corresponding 3D chemical structures, molecular weights, cLogP hydrophobicities, unitless DWBEL docking-scores and kcal/mol and nM ADV affinities. The file can be opened in freely-available either MolSoft (https://www.molsoft.com/download.html) or DW (https://openmolecules.org/datawarrior/download.htm).
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36F13L2.sdf
Description
36F13L2.sdf. Data from 36 Tecovirimat-derived non-toxic fitted-top-children consensus of < -90 DWBEL and < -10 kcal/mol ADV (Figure 3 F13L2 and 3532F13L2.sdf). The file contains generated conformer DWBEL order (ID), with their corresponding 3D chemical structures, molecular weights, cLogP hydrophobicities, unitless DWBEL docking-scores and kcal/mol and nM ADV affinities. The file can be opened in freely-available either MolSoft (https://www.molsoft.com/download.html) or DW (https://openmolecules.org/datawarrior/download.htm).
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32F13L1.pse
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32 DWBEL+ADV consensus top-children conformers targeting F13L1 (PyMol 2.5.3).
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36F13L2.pse
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36F13L2.pse. 36 DWBEL+ADV consensus top-children conformers targeting F13L2 (PyMol 2.5.3).
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Phyton script to select DWBEL+ ADV children
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Script to select those highest affinities of top-children from both DWBEL and ADV of Figure 3.
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MPXV F13L evolutionary docking.mp4
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a short video describing the steps followed in the manuscript: models, mutations and mutants, DWBEL co-evolution and ADV consensus docking.
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DWBEL.mp4
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screen recordings of a DWBEL co-evolution
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ADV5.mp4
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screen recordings of a PyRx/OBabel/ADV consensus docking of the children generated in DWBEL co-evolution
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