Before and after AlphaFold2: An overview of protein structure prediction

Frontiers in Bioinformatics, Journal Year: 2023, Volume and Issue: 3

Published: Feb. 28, 2023

Three-dimensional protein structure is directly correlated with its function and determination critical to understanding biological processes addressing human health life science problems in general. Although new structures are experimentally obtained over time, there still a large difference between the number of sequences placed Uniprot those resolved tertiary structure. In this context, studies have emerged predict by methods based on template or free modeling. last years, different been combined overcome their individual limitations, until emergence AlphaFold2, which demonstrated that predicting high accuracy at unprecedented scale possible. Despite current impact field, AlphaFold2 has limitations. Recently, language models promised revolutionize structural biology allowing discovery only from evolutionary patterns present sequence. Even though these do not reach accuracy, they already covered some being able more than 200 million proteins metagenomic databases. mini-review, we provide an overview breakthroughs prediction before after emergence.

Language: Английский

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AlphaFold, allosteric, and orthosteric drug discovery: Ways forward

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(6), P. 103551 - 103551

Published: March 11, 2023

Drug discovery is arguably a highly challenging and significant interdisciplinary aim. The stunning success of the artificial intelligence-powered AlphaFold, whose latest version buttressed by an innovative machine-learning approach that integrates physical biological knowledge about protein structures, raised drug hopes unsurprisingly, have not come to bear. Even though accurate, models are rigid, including pockets. AlphaFold's mixed performance poses question how its power can be harnessed in discovery. Here we discuss possible ways going forward wielding strengths, while bearing mind what AlphaFold cannot do. For kinases receptors, input enriched active (ON) state better chance rational design success.

Language: Английский

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Impact of AlphaFold on structure prediction of protein complexes: The CASP15‐CAPRI experiment

Proteins Structure Function and Bioinformatics, Journal Year: 2023, Volume and Issue: 91(12), P. 1658 - 1683

Published: Oct. 31, 2023

Abstract We present the results for CAPRI Round 54, 5th joint CASP‐CAPRI protein assembly prediction challenge. The offered 37 targets, including 14 homodimers, 3 homo‐trimers, 13 heterodimers antibody–antigen complexes, and 7 large assemblies. On average ~70 CASP predictor groups, more than 20 automatics servers, submitted models each target. A total of 21 941 by these groups 15 scorer were evaluated using model quality measures DockQ score consolidating measures. performance was quantified a weighted based on number acceptable or higher group among their five best models. Results show substantial progress achieved across significant fraction 60+ participating groups. High‐quality produced about 40% targets compared to 8% two years earlier. This remarkable improvement is due wide use AlphaFold2 AlphaFold2‐Multimer software confidence metrics they provide. Notably, expanded sampling candidate solutions manipulating deep learning inference engines, enriching multiple sequence alignments, integration advanced modeling tools, enabled top performing exceed standard version used as yard stick. notwithstanding, remained poor complexes with antibodies nanobodies, where evolutionary relationships between binding partners are lacking, featuring conformational flexibility, clearly indicating that remains challenging problem.

Language: Английский

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Artificial intelligence as a tool for creativity

Journal of Creativity, Journal Year: 2024, Volume and Issue: 34(2), P. 100079 - 100079

Published: Feb. 5, 2024

The release of ChatGPT has sparked quite a bit interest about creativity in the context artificial intelligence (AI), with theorizing and empirical research asking questions nature (both human artificially-produced) valuing work produced by humans means. In this article, we discuss one specific scenario identified community – co-creation, or use AI as tool that could augment creativity. We present emerging relevant to how can be used on continuum four levels creativity, from mini-c/creativity learning little-c/everyday Pro-C/professional Big-C/eminent discussion, is defined broadly, not include only large language models (e.g., ChatGPT) which might approach general AI, but also other computer programs perform tasks typically understood requiring intelligence. conclude considering future directions for across c's.

Language: Английский

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Plant cell wall-mediated disease resistance: Current understanding and future perspectives

Molecular Plant, Journal Year: 2024, Volume and Issue: 17(5), P. 699 - 724

Published: April 9, 2024

Language: Английский

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Review of AlphaFold 3: Transformative Advances in Drug Design and Therapeutics

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: July 2, 2024

Google DeepMind Technologies Limited (London, United Kingdom) recently released its new version of the biomolecular structure predictor artificial intelligence (AI) model named AlphaFold 3. Superior in accuracy and more powerful than predecessor 2, this innovation has astonished world with capacity speed. It takes humans years to determine various proteins how shape works receptors but 3 predicts same seconds. The version's utility is unimaginable field drug discoveries, vaccines, enzymatic processes, determining rate effect different biological processes. uses similar machine learning deep models such as Gemini (Google Limited). already established itself a turning point computational biochemistry development along receptor modulation development. With help this, researchers will gain unparalleled insights into structural dynamics their interactions, opening up avenues for scientists doctors exploit benefit patient. integration AI like 3, bolstered by rigorous validation against high-standard research publications, set catalyze further innovations offer glimpse future biomedicine.

Language: Английский

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A review on structure-function mechanism and signaling pathway of serine/threonine protein PIM kinases as a therapeutic target

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 270, P. 132030 - 132030

Published: May 3, 2024

Language: Английский

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Exploring the antifungal potential of Cannabis sativa-derived stilbenoids and cannabinoids against novel targets through in silico protein interaction profiling

Frontiers in Chemistry, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 6, 2025

Cannabinoid and stilbenoid compounds derived from Cannabis sativa were screened against eight specific fungal protein targets to identify potential antifungal agents. The proteins investigated included Glycosylphosphatidylinositol (GPI), Enolase, Mannitol-2-dehydrogenase, GMP synthase, Dihydroorotate dehydrogenase (DHODH), Heat shock 90 homolog (Hsp90), Chitin Synthase 2 (CaChs2), Mannitol-1-phosphate 5-dehydrogenase (M1P5DH), all of which play crucial roles in survival pathogenicity. This research evaluates the binding affinities interaction profiles selected cannabinoids stilbenoids with these using molecular docking dynamics simulations. ligands highest identified, their pharmacokinetic analyzed ADMET analysis. results indicate that synthase exhibited affinity Cannabistilbene I (-9.1 kcal/mol), suggesting hydrophobic solid interactions multiple hydrogen bonds. Similarly, demonstrated significant kcal/mol). In contrast, such as Cannabinolic acid 8-hydroxycannabinolic moderate affinities, underscoring variability strengths among different proteins. Despite promising silico results, experimental validation is necessary confirm therapeutic potential. lays a foundation for future studies, emphasizing importance evaluating properties, multi-target

Language: Английский

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Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to early lethality in mice

Published: Jan. 16, 2025

Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either as a homodimer, or more active BMP4/7 heterodimer. BMPs are generated inactive precursor proteins that dimerize cleaved to generate the bioactive ligand prodomain fragments. In humans, heterozygous mutations within of BMP4 associated with birth defects. We studied effect two these (p.S91C p.E93G), which disrupt conserved FAM20C phosphorylation motif, on activity. compared activity homodimers heterodimers from BMP4, S91C E93G in Xenopus embryos found reduce but not heterodimers. Bmp4 knock-in mice S91C/S91C die by E11.5 display reduced BMP multiple tissues including heart at E10.5. Most E93G/E93G before weaning -/E93G mutants prenatally absent eyes, ventral body wall closure Mouse embryonic fibroblasts (MEFs) isolated show accumulation protein, levels relative MEFs wild type littermates. Because Bmp7 is expressed MEFs, unprocessed protein carrying most likely reflects an inability cleave homodimers, leading vivo. Our results suggest required for proteolytic activation

Language: Английский

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State-of-the-Art in the Drug Discovery Pathway for Chagas Disease: A Framework for Drug Development and Target Validation

Research and Reports in Tropical Medicine, Journal Year: 2023, Volume and Issue: Volume 14, P. 1 - 19

Published: June 1, 2023

Abstract: Chagas disease is the most important protozoan infection in Americas, and constitutes a significant public health concern throughout world. Development of new medications against its etiologic agent, Trypanosoma cruzi , has been traditionally slow difficult, lagging comparison with diseases caused by other kinetoplastid parasites. Among factors that explain this are incompletely understood mechanisms pathogenesis T. complex set interactions host chronic stage disease. These demand performance variety vitro vivo assays as part any drug development effort. In review, we discuss recent breakthroughs understanding parasite's life cycle their implications search for chemotherapeutics. For this, present framework to guide discovery efforts disease, considering state-of-the-art preclinical models recently developed tools identification validation molecular targets. Keywords: development, screenings, target, animal

Language: Английский

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