Co-evolved ligands to ORF8. Could they reduce SARS-COV-2-excesive inflammation? DOI Creative Commons
Melissa Belló-Pérez, Julio Coll

Published: Dec. 19, 2023

ORF8 is an asymmetric-homodimer SARS-COV-2 accessory protein implicated in excesive human inflammation causing numerous deaths. There no approved drug targeting ORF8, nor it known whether any anti-ORF8 drugs could reduce inflammation. Computationally combining ligand co-evolution of parent molecules with affinity-consensus docking, children candidates for docking to cavities were generated. Targeting the homodimer interface highest affinity scaffolds, hundreds grandchildren predicting nanoMolar affinities, unique high specificities and low toxicity risks Although remaining hypothetical without experimental confirmation, this constitute a new methodological attempt search drug-like interfere SARS-COV-2-dependent excessive

Language: Английский

Generation of docking ligands to F13L mutations isolated in MonkeyPoxVirus-infected patients resistant to Tecovirimat-treatment DOI Creative Commons
Julio Coll

Published: Jan. 4, 2024

Alternative drugs are actively searched because of the recent identification F13L mutations in MonkeyPox Virus (MPXV)-infected patients with resistances to Tecovirimat-treatment. Aiming help on these searches, computational strategies generate rather than screen for new drug-like ligand candidates were explored here. Targeting F13L-mutant representative models, thousands fitted-children ligands predicted by i) co-evolutions from Tecovirimat parent molecule, and ii) models limited pooling most abundant isolated Tecovirimat-treated patients. Children-fitting docking-cavities novel scaffolds, nanoMolar affinities, high specificities, absence known toxicities conservation their parent-docking cavities. Despite limitations, such proved-on-concept similar might be fine-tuned explore prevalent Tecovirimat-resistance mutants

Language: Английский

Citations

2
Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities DOI Creative Commons
Julio Coll

Published: Jan. 17, 2024

Human potassium channels (Kir) are implicated in numerous dysfunction diseases genetically affecting cardiovascular, skeletal-muscle and/or synaptic-neuronal functions. Variations Kir sequences, organ distribution differences and toxicity of some their known inhibitors, require alternative drugs to interfere specifically with each human molecular species. In this work, a prokaryotic asymmetric transmembrane homotetramer (K+) channel protein highly homologous Kirs has been used as model. Computational methods combining parent co-evolutions confirmed by consensus docking, were explored possible prove-of-concept generate rather than screen for KcsA docking-ligands. The explorations the central cavity interface lipid-binding shallow-grooves, predicted specific novel scaffolds low-toxicity risks, displaying hundreds variations new within nanoMolar-ranged affinities. Experimental validation additional computational research on could be attempted future.

Language: Английский

Citations

2
Star-shaped conformers generated by co-evolutionary docking predict cross-fitting glycoprotein trimer pre-fusion interfaces on VHSV fish rhabdovirus DOI Creative Commons
Julio Coll

Published: April 26, 2024

Despite the abundant diseases caused by rhabdoviruses on plants, animals and men, there are no approved therapeutic drugs. This work targeted viral hemorrhagic septicemia viruses (VHSV), a group of representative causing devastating world-wide fish farmed-species. In particular, their glycoprotein (gpGVHSV) trimers were computationally at its earliest pre-fusion inner interface. Co-evolution initiated from an optimized 2D-molecular parent corresponding gpGVHSV -conformer 3D cavity, generated tens thousands raw-children, selected hundreds cross-fitting conformer variations in few scaffolds. Their predicted drug-like high affinities nanoMolar ranges, low toxicities targeting interface confirmed independent algorithms

Language: Английский

Citations

1
Co-evolution ligands to Tecovirimat-resistant F13L mutations of MonkeyPox Virus DOI Creative Commons
Julio Coll

Published: Aug. 30, 2024

Because of the emergence F13L mutations in MonkeyPox Virus (MPXV)-infected patients with resistances to Tecovirimat-treatment, alternative drugs are actively searched. Aiming help on these searches, computational strategies generate rather than screen for new drug-like ligand candidates were explored here. Ligands predicted by i) thousands Tecovirimat-derived children generated co-evolution fitting docking cavities at either F13L1 or F13L2, and ii) top-children F13L-mutant resistant models isolated from Tecovirimat-treated patients. Top-children-fitting docking-cavities novel scaffolds, nanoMolar affinities, high specificities, absence known toxicities similar conservation their targeted Tecovirimat-docking cavities. Despite limitations, proved-on-concept might be fine-tuned explore most prevalent Tecovirimat-resistance mutations.

Language: Английский

Citations

1
Tailoring evolved-ligands to Plasmodium circumsporozoite-protein DOI Creative Commons
Julio Coll

Published: June 3, 2024

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 complement that tool-box, remain underdeveloped. Despite tridimensional coat of disordered-repeats, computational predictions mimicking natural co-evolution tailored evolved ligands adapt ordered CSP cavities. Tens thousands parent-generated raw-candidates selected hundreds fitted-children conformers predicting low nanoMolar affinities, toxicities, and cross-docking N-terminal signal peptide with C-terminal α-helices or docking These repeat-independent predictions, could provide some proof-of-concept examples for basic in vitro experimentation

Language: Английский

Citations

0
Co-evolved ligands to ORF8. Could they reduce SARS-COV-2-excesive inflammation? DOI Creative Commons
Melissa Belló-Pérez, Julio Coll

Published: Dec. 19, 2023

ORF8 is an asymmetric-homodimer SARS-COV-2 accessory protein implicated in excesive human inflammation causing numerous deaths. There no approved drug targeting ORF8, nor it known whether any anti-ORF8 drugs could reduce inflammation. Computationally combining ligand co-evolution of parent molecules with affinity-consensus docking, children candidates for docking to cavities were generated. Targeting the homodimer interface highest affinity scaffolds, hundreds grandchildren predicting nanoMolar affinities, unique high specificities and low toxicity risks Although remaining hypothetical without experimental confirmation, this constitute a new methodological attempt search drug-like interfere SARS-COV-2-dependent excessive

Language: Английский

Citations

0