![Author ORCID: We display the ORCID iD icon alongside authors names on our website to acknowledge that the ORCiD has been authenticated when entered by the user. To view the users ORCiD record click the icon. [opens in a new tab]](https://chemrxiv.org/engage/assets/public/chemrxiv/images/logos/orcid.png)
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
Title
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.
Actions
Title
1769F13L1.sdf
Description
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).
Actions
Title
3532F13L2.sdf
Description
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).
Actions
Title
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).
Actions
Title
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).
Actions
Title
32F13L1.pse
Description
32 DWBEL+ADV consensus top-children conformers targeting F13L1 (PyMol 2.5.3).
Actions
Title
36F13L2.pse
Description
36F13L2.pse. 36 DWBEL+ADV consensus top-children conformers targeting F13L2 (PyMol 2.5.3).
Actions
Title
Phyton script to select DWBEL+ ADV children
Description
Script to select those highest affinities of top-children from both DWBEL and ADV of Figure 3.
Actions
