![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
This work computationally explored the possible protection of human A3G hypermutation, one of the most potent human natural inhibitors of human immunodeficiency viral (HIV) infections. This work focused on the possible inhibition of HIV Viral infectivity factor (Vif) which destroys A3G in natural infections. Due to the different assemblies of Vif with several human proteins, development of antiVif inhibitors as drugs have been limited. To propose new antiVif molecules for experimental testing, docking to recently described Vif-sA3G interfaces, were explored here by evolutionary docking. Tens of thousands of new molecular children were generated from previous antiVif and star-like parent molecules. Hundreds of children fitting Vif-cavity sA3G interfaces were then selected by consensus docking. Results predicted low-toxicity top-children displaying ~ 10-100 fold higher consensus docking-affinities including targeting similar amino acids than those previously described for antiVif drugs inhibiting HIV. Consensus top-children are proposed to test for possible experimental restoration of A3G hypermutation in the presence of HIV-Vif infections
Supplementary materials
Title
Graphycal Abstract of the VifblueVifredsA3G + RNA simplified model.pse
Description
GraphycalAbstract.pse. 3D structural view of the VifblueVifredsA3G + RNA homo-monomer modified from 8h0i.pdb (Figure S1). Their α-helices were drawn as cylinders for clarity. Grey cartoons, human sA3G. Blue cylinders, HIV-Vifblue . Red cylinders, HIV-Vifred . Yellow cylinders, human CBF. Black sticks, RNA20 short sequence. Red spheres, some children ADV blind-docked to VifblueVifredsA3G defining some docking cavities
Actions
Title
DWBEL parents 10Vif-mmff94s+.sdf
Description
10Vif-mmff94s+.sdf. Data from 10 anti-Vifs previously reported by Bennett et al 24 and Sharkey et al 25 . The file contains the 3D chemical structures minimized by DW mmff94s+ force-field conformers to preserve 2D geometry during ADV docking , molecular weights, and cLogP hydrophobicities. The *.sdf file can be opened for text on text editors and for 2D/3D molecular structures on MolSoft (https://www.molsoft.com/download.html) or DW (https://openmolecules.org/datawarrior/download.htm).
Actions
Title
DWBEL parents 36star-mmff94s+.sdf
Description
36star-mmff94s+.sdf. Data from 3-fold star-like home-designed molecules of different molecular weights45, 47 . The file contains 3D chemical structures minimized by DW mmff94s+ force-field conformers to preserve 2D geometry during ADV docking , molecular weights, and cLogP hydrophobicities. The *.sdf file can be opened for text on text editors and for 2D/3D molecular structures on MolSoft (https://www.molsoft.com/download.html) or DW (https://openmolecules.org/datawarrior/download.htm).
Actions
Title
18consensusfromVif8.sdf.
Description
18consensusfromVif8.sdf. Top-children predicting high-affinity consensus in both DWBEL and ADV were extracted from the non-toxic fitted-children derived from Vif8 (Figure 1) by home-made PyMol/Python scripts. Such consensus resulted in 18 top-children. The *.sdf file can be opened for text on text editors and for 2D/3D molecular structures on MolSoft (https://www.molsoft.com/download.html) or DW (https://openmolecules.org/datawarrior/download.htm).
Actions
Title
26consensusfrom30.sdf.
Description
26consensusfrom30.sdf. Top-children predicting high-affinity consensus in both DWBEL and ADV were extracted from the non-toxic fitted-children derived from star30 (Figure 1) by home-made PyMol/Phyton scripts. Such consensus resulted in 26 top-children. The *.sdf file can be opened for text on text editors and for 2D/3D molecular structures on MolSoft (https://www.molsoft.com/download.html) or DW (https://openmolecules.org/datawarrior/download.htm).
Actions
Title
Video summarizing this work
Description
HIV-Vif.mp4. A video summarizing the targeted VifblueVifredsA3G ± RNA homo-monomer, grid design, DWBEL co-evolutions, ADV-docking and predicted results. The file last ~14 min. The file can be open in any video program.
Actions
