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Abstract
To prevent malaria deathly infections, the Plasmodium circumsporozoite major protein (CSP) have been targeted world-wide to develop most recent vaccines inducing anti-CSP antibodies. In contrast, drug-like anti-CSP to complement that anti-CSP tool-box, remain underdeveloped. Despite the tridimensional coat of disordered-repeats, computational predictions mimicking natural co-evolution tailored evolved ligands to adapt to most ordered CSP cavities. Tens of thousands of parent-generated raw-candidates selected hundreds of fitted-children conformers predicting low nanoMolar affinities, low toxicities, and cross-docking N-terminal signal peptide with C-terminal α-helices or docking C-terminal cavities. These repeat-independent drug-like predictions, could provide some proof-of-concept examples for basic in vitro experimentation
Supplementary materials
Title
GraphycalAbstract.pse
Description
The mRNA of Plasmodium falciparum reference 3D7-strain circumsporozoite protein (PF3D7_0304600), XM_001351086.1 was submitted to alphafold. One of the most representative predicted models was selected for this study (Gray cartoons). Amino acid 310-375 residues aligned to 10 CSP models Plasmodium species showed high conservation of their 338C-369C and 342C-374C disulphide bonds (Table S2). Red spheres, Representative examples of top-children targeting two repeat-independent CSP cavities: cross-docking N- (SP) with C-terminal α-helices and C-terminal domain.
Actions
Title
StarlikeLigands.sdf
Description
Contains 3-fold star-like ligand molecules manually designed in MolSoft by 2D drawing different central atoms, rings and sizes including 3-6 carbon arms ended by amino and carboxy structures (alanines). To conserve their 2D geometries during ADV docking, optimal conformers were generated by the DW / mmff94s+ force-field algorithm49 .
Actions
Title
1301CSP.dwar
Description
This *.dwar DW table contains 1301 children generated from the 24L parent targeting CSP by 2 runs of DWBEL (DW-ID) and their corresponding ADV affinities (ADV-NN). The table is provided with threshold slider-filters to select for (309-374 residues)threshold combinations (https://openmolecules.org/datawarrior/download.html)
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Title
6970CSP.dwar
Description
This *.dwar DW table contains 6970 children generated from the 24L parent targeting CSP by 6 runs of DWBEL (DW-ID) and their corresponding ADV affinities (ADV-NN). The table is provided with threshold slider-filters to select for threshold combinations (https://openmolecules.org/datawarrior/download.html)
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Title
1770CSPmin.dwar
Description
This *.dwar DW table contains 1770 children targeting CSPmin (309-374 residues) by DWBEL (DW-ID) derived from the 384NN parent (derived from the 157NN parent) and their corresponding ADV affinities (ADV-NN). The table is provided with threshold slider-filters to select for threshold combinations (https://openmolecules.org/datawarrior/download.html)
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Title
19top.pse
Description
Contains top-children ADV conformers docked to full-length CSP from the 1301 DWBEL 1301 (2 runs). To view the docked individual children click on the NN number 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
84top.pse
Description
Contains top-children ADV conformers docked to full-length CSP from the 6970 DWBEL (6 runs). To view the docked individual children click on the NN number 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
18top.pse
Description
Contains top-children ADV conformers docked to CSPmin (309-374 residues) from the 1770 DWBEL (3 runs). To view the docked individual children click on the NN number 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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