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Abstract
The respiratory syncytial virus (RSV) causes abundant annual fatalities on young children and elder adults by infecting human cells mediated by RSV fusion (F) surface homotrimeric proteins. Despite their RSV fusion in vitro inhibitors, anti-F therapeutic molecules are not yet clinically available because of emergent resistant mutations. Here, alternative therapeutic strategies are explored to dock mutated F protein models. For that thousands of trimeric drug-like candidates were computationally generated/selected by parent-children co-evolution. New top-children candidates may help experimental tests since they display 3-fold star-like molecules fitting similar trimeric F cavities than previous in vitro inhibitors but improved higher sub-nanoMolar affinities. Additionally, some top-children also successfully targeted F mutations previously implicated in RSV fusion drug-resistances
Supplementary materials
Title
GraphycalAbstract.pse
Description
Bottom-view of the RSV F crystallographic model showing its homotrimer top-to-bottom central cavity complexed with TMC353121 (5ea5.pdb)16. The α-helices were drawn as cylinders. Carbon grey cartoons, trimer chains at different intensities. Yellow cylinders, α-helices containing part of the HRB heptad-repeats located above the transmembrane α-helices. Green spheres, amino acid side chains of residues 140, 486-489 (drug-cavity). Red spheres, example of docked fusion-inhibitor drug (TMC353121).
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Title
3594BTA.dwar
Description
Data from the 3549 BTA-derived non-toxic fitted-children from Figure 1, were tabulated in this file. The file contains all randomly generated 3D conformer order (ID), with their corresponding 2D and 3D chemical structures, molecular weights, cLogP hydrophobicities, order number by docking score (NN) and their ADV affinity in kcal/mol and calculated ~ nM. The file can be opened in freely-available DW program (https://openmolecules.org/datawarrior/download.htm).
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Title
BTA.pse
Description
BTA.pse. The BTA anti-F fusion drug from 5ea6.pdb, was drawn in the last version of PyMol. The file data were drawn in PyMol 2.5.3 using the 5ea6.pdb as the F model. Red sticks, BTA9881
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Title
BTA100tops.pse.
Description
The 100 top-children conformers derived from DWBEL from the BTA anti-F fusion drug from Figure 1, tabulated in the 3548BTA.dwar. The file data were drawn in PyMol 2.5.3 using the 5ea6.pdb as the F model
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Title
979BTAmutations.dwar
Description
979 BTA top-children ADV docked to wild-type F (Figure 1) and 23 fusion-inhibitor resistant mutations (F140I, F488I, D489Y and L138I, L141W, G143S, T144A, T323A, I379V, V384I, D388Y, D392G, K394R, M396I, T397S, S398L, K399N, T400I, D401E, I474T, V482A, E487D, S509I). The Table was provided with threshold ADV affinity slider-filters adjusted for selecting the 7 top-children. The file can be opened in freely-available DW program (https://openmolecules.org/datawarrior/download.htm).
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