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Abstract
To prevent malaria deathly infections, the Plasmodium circumsporozoite- protein (CSP) have been targeted to develop most recent vaccines inducing anti-CSP antibodies with ~ 70 % protection. In contrast, anti-CSP drug-like small-molecules remain underdeveloped to possible complement such anti-CSP tool-box. Computational predictions mimicking natural co-evolution are described here trying to bypass the tridimensional shield-coat of CSP disordered-repeats. Tens of thousands of raw-children were generated by co-evolution from home-designed molecular parents. Hundreds of CSP fitted-children predicting low molecular weights, hydrophilicities, toxicities and nanoMolar affinities, were identified. Some of the resulting non-toxic fitted-children either cross-docked the CSP signal peptide and C-terminal α-helices and/or targeted other ordered CSP cavities. These repeat-independent drug-like anti-CSP evolved-ligand predictions, 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.
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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 .
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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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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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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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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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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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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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Title
- DWBELfirstlast-PyMOLpredictions.mp4
Description
Visualizes in PyMol some of the first (higher docking-scores) and last (lower docking-scores) conformers generated by DWBEL after one run from the star21 parent example. The derivatives were co-evolved with preference criteria to: <600g/mol, <4 logP and non-toxicity risks.
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- 5SCP-alphafoldmodels.pse
Description
Contains 5 models obtained by 3D-molecular predictions by alphafold of the CSP sequence. The models were aligned so that can be merged in PyMol after opening the *.pse file in one of the latest PyMol 2023-24.
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Title
- DWBEL-1448predictions.mp4
Description
Visualizes in DW the 1448 conformers of one run example beginning with star21 parent. The DWBEL predicted children derivatives were co-evolved targeting preferences: <600g/mol, <4 logP and non-toxicity risks. Results are shown from the first star21 to the last lower docking-scores (higher affinities)
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Title
- DWBELhowto.mp4.
Description
Describes the 36 home-designed pseudoligands, and their use for affinity improvement by fitness evolution by DWBEL from the star21 example. Includes the final saving of raw-fitted children and non-toxic filtered children into DW *.dwar files and their mmff94s+ force-field treated *.sdf file to improve geometries for ADV docking.
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Title
- NANPmodelmimics.mp4
Description
Mimicking the flexibility of the NANP-loops by sequential showing the different structures predicted by alphafold modeling in PyMol. To mention the similar positions maintained by the CSP alpha-helices.
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Title
- NANPmodelrolling.mp4
Description
Mimicking the flexibility of the NANP-loops by rolling the different structures predicted by alphafold modeling. To mention the similar positions maintained by the CSP alpha-helices.
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