CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson’s Disease Associated Protein

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(22), P. 8521 - 8536

Published: Nov. 5, 2024

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field computational hit-finding. Here we report results inaugural challenge which 23 teams each selected up 100 commercially available compounds that they predicted would bind WDR domain Parkinson's disease target LRRK2, with no known ligand and only an apo structure PDB. lack binding data presumably low druggability is hit finding methods. Of 1955 molecules by participants Round 1 challenge, 73 were found LRRK2 SPR assay KD lower than 150 μM. These advanced 2 expansion phase, where 50 analogs. Binding was observed two orthogonal assays for seven chemically diverse series, affinities ranging from 18 140 successful workflows varied their screening strategies techniques. Three used molecular dynamics produce conformational ensemble targeted site, three included fragment docking step, implemented generative design strategy five one or more deep learning steps. #1 reflects highly exploratory phase drug adopted strikingly diverging strategies. Machine learning-accelerated methods achieved similar brute force (e.g., exhaustive) docking. First-in-class, experimentally confirmed rare weakly potent, indicating recent advances not sufficient effectively address challenging targets.

Language: Английский

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Prediction of SafD adhesin strong binding peptides for pilus proteins assembly suppression in the prevention of Salmonella-induced biofilm formation using virtual mutagenesis studies

In Silico Pharmacology, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 10, 2025

Language: Английский

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Combined usage of ligand- and structure-based virtual screening in the artificial intelligence era

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 283, P. 117162 - 117162

Published: Dec. 11, 2024

Language: Английский

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CACHE Challenge #1: targeting the WDR domain of LRRK2, a Parkinson's Disease associated protein.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 18, 2024

ABSTRACT The CACHE challenges are a series of prospective benchmarking exercises meant to evaluate progress in the field computational hit-finding. Here we report results inaugural #1 challenge which 23 teams each selected up 100 commercially available compounds that they predicted would bind WDR domain Parkinson’s disease target LRRK2, with no known ligand and only an apo structure PDB. lack binding data presumably low druggability is hit finding methods. Seventy-three 1955 procured molecules bound LRRK2 SPR assay K D lower than 150 μM were advanced expansion phase where 50 analogs each. Binding was observed two orthogonal assays affinities ranging from 18 140 for seven chemically diverse series. successful workflows varied their screening strategies techniques. Three used molecular dynamics produce conformational ensemble targeted site, three included fragment docking step, implemented generative design strategy five one or more deep learning steps. reflects highly exploratory drug participants sometimes adopted strikingly diverging strategies. Machine-learning accelerated methods achieved similar brute force (e.g. exhaustive) docking. First-in-class, experimentally confirmed rare weakly potent, indicating recent advances not sufficient effectively address challenging targets.

Language: Английский

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Prediction of SafD adhesin strong binding peptides for pilus proteins assembly suppression in the prevention of Salmonella-induced biofilm formation using virtual mutagenesis studies

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 12, 2024

Clinical isolates of Salmonella enterica contain Saf pili that establish initial bacterial attachment with the human epithelium to form biofilms which are a common cause several abdominal complications. Due rise in antibiotic-resistant strains bacteria, an alternate strategy inhibiting contact epithelial layers is well-studied. undergo chaperone-usher pathway assembly mechanism generate its host-recognizing functional form, SafDAA. Preventing biogenesis by targeting SafD and SafA proteins polymerization will prevent host recognition. In this study, virtual mutagenesis studies using recently reported X-ray crystal structure N-terminal peptide co-crystallized led design peptides exhibit enhanced binding compared native peptide. Virtual alanine protein–peptide interaction identified hotspot residues. Molecular dynamics simulations free energy calculations key pairwise interactions between designed SafD. addition, library 110 predicted bind strongly prepared can serve as excellent resource for discovery novel SafD-binding peptides. This work provided new insights into anti-virulence therapies enterica.

Language: Английский

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