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Abstract
The ORCO odor co-receptors are homotetrameric membrane proteins present in the insect olfactory neurons, such as those in Anopheles sp., one of the main malarian vectors. For mosquitoes to detect specific chemicals, common ORCO are required to complex with individual hundreds of specific olfactory receptors (OR). The ORCO+OR complexes allow female mosquitos to find appropriated male-mating, human-blood for egg development and wet-places for egg deposition. Volatil chemicals bind ORCO’s monomeric cavities to allosterically affect the tetrameric ionic flow required for OR odor-detection. In this work, new ligands have been derived from anti-ORCO previously described hit parents by evolutionary docking to select those children fitting into the hee desribed ORCO's monomeric cavities. Hundreds of fitted-children predicted low-toxicities, low microMolar affinities, and high vapor-pressures (volatibility). The new hit-derived top-children cross-docked similar ORCO α-helices than those previously reported hits but with ~ 10-100 fold higher docking affinities. Dozens of the top-children are proposed here for experimental tests as candidates for new mosquito volatile repellents and/or reproduction inhibitors.
Supplementary materials
Title
GraphycalAbstract.pse describing the ORCO tetramer
Description
3D molecular structural bottom-view of the Anopheles homo tetramer modeled from the Apocrypta bakeri ORCO (6C70.pdb)22 . The 3D Alignment shos an identity of 0.2 Å with the Aedes aegypty Swiss model. Grey cartoons, α-carbons, α-helices drawn as cylinders. Yellow cylinders corresponded to α-helix residues 452-471 surrounding the central tetrameric ion channel pore. Red spheres, ORCO V469 and L473 amino acids binding the VUAA1 activator of ion flow through the homotetramer central channel pore. Green cylinders, monomer α-helices implicated in the allosteric docking cavities targeted by anti-ORCOs, corresponding to: S3 (117-154), S4 (193-243) and S6 (378-420).
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Title
HGNN.dwar description of molecular characteristics of the initial parents
Description
Molecular characteristics of 4 volatile chemicals of different molecular weights with experimentally demonstrated anti-ORCO properties19 that were selected for ADV blind-docking to the Anopheles ORCO monomeric model. They defined their corresponding 2D-parents and 3D-cavities for DWBEL co-evolutions. Their optimal 3D conformers were generated by the DW / mmff94s+ force-field algorithm24 that best preserved their 2D geometries after PyRx Obabel minimization, pdbqt generation and ADV blind-docking
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Title
Fig2Ligs.pse. Hexanoic derived top children structures
Description
The hexanoic-derived VP+ADV 35 top-children docked to the Anopheles ORCO monomer of Figure 2 were drawn in PyMol together with their targeted ORCO α-helices, and some of their nearby aminoacids (4 Å) (Supplementary Materials / nearbyAa.py). Colored sticks, top-children surrounding the ORCO monomer α-helices implicated into their docking: S2 (69-107), S3 (117-154), S4 (193-243), S5 (320-374), S6 (378-420). Docking site A (top). Docking site B (bottom). To view each of the docked individual conformers or their targeted nearby amino acids click on their NN2 numbers to the right of the PyMol scene after opening the *.pse file in one of the latest PyMol 2023-24 versions.
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Title
nearbyAa.py script to generate nearby amino acids in a txt file
Description
A PyMol / Python script to identify the amino acid residues and their chain positions within 4 Å of the docked ligand conformers and save the information into a nearbyligand.txt file. To run, all files should be copied into the same directory including the *.pdbqt ligand conformers, the *.pdb, *.pdbqt or *pse targeted protein and the *.py script. To run the script requires a text editor (i.e., NotePad or EditPlus) for typing and saving the nearby.py file with the PyMol names of the Ligand and the targeted protein. Finally, the script can be run by opening the targeted protein file in PyMol and clicking on PyMol/File/Run Script/nearbyAa.py.
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Title
35Lig.dwar hexanoic derived top children
Description
This DW Table contains 35 hexanoic-derived top-children targeting Anopheles ORCO monomers, ADV docked conformer structures, molecular weights (MW), hydrophobicities (cLogP), targeted A or B sites, and their predictions of DWBEL docking scores (unitless), VP ( mmHg) and ADV affinities (kcal/mol and ~nM). The DW Table was provided with threshold slider-filters to select different combinations of conformers. The *.dwar files can be opened within freely availble DW progam (https://openmolecules.org/datawarrior/download.html
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