Quantitative Estimate Index for Early-Stage Screening of Compounds Targeting Protein-Protein Interactions

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(20), С. 10925 - 10925

Опубликована: Окт. 10, 2021

Drug-likeness quantification is useful for screening drug candidates. Quantitative estimates of drug-likeness (QED) are commonly used to assess quantitative efficacy but not suitable compounds targeting protein-protein interactions (PPIs), which have recently gained attention. Therefore, we developed a estimate index PPIs (QEPPI), specifically early-stage PPI-targeting compounds. QEPPI an extension the QED method drugs that models physicochemical properties based on information available drugs/compounds, those reported act PPIs. FDA-approved and in iPPI-DB, comprise PPI inhibitors stabilizers, were evaluated using QEPPI. The results showed more than early was also considered extended concept “Rule-of-Four” (RO4), inhibitor index. We discriminatory performance RO4 datasets PPI-target F-score other indices. F-scores 0.451 0.501, respectively. better enabled discovery. Hence, it can be as initial filter efficiently screen

Язык: Английский

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Design of Peptide-Based Protein Degraders via Contrastive Deep Learning

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Май 24, 2022

A bstract Therapeutic modalities targeting pathogenic proteins are the gold standard of treatment for multiple disease indications. Unfortunately, a significant portion these considered “undruggable” by small molecule-based approaches, largely due to their disordered nature and instability. Designing functional peptides undruggable targets, either as standalone binders or fusions effector domains, thus presents unique opportunity therapeutic intervention. In this work, we adapt recent models contrastive language-image pre-training (CLIP) devise unified, sequence-based framework design target-specific peptides. Furthermore, leveraging known experimental binding scaffolds, create streamlined inference pipeline, termed Cut&CLIP , that efficiently selects downstream screening. Finally, experimentally fuse candidate E3 ubiquitin ligase domains demonstrate robust intracellular degradation protein targets in human cells, motivating further development our technology future clinical translation.

Язык: Английский

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Mixed Stereochemistry Macrocycle Acts as a Helix-Stabilizing Peptide N-Cap

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(35), С. 24348 - 24357

Опубликована: Авг. 25, 2024

Interactions between proteins and α-helical peptides have been the focus of drug discovery campaigns. However, large interfaces formed multiple turns an α-helix a binding protein represent significant challenge to inhibitor discovery. Modified featuring helix-stabilizing macrocycles shown promise as inhibitors these interactions. Here, we tested ability N-terminal side-chain thioether-cyclized inhibit Mcl-1, by screening trillion-scale library. The enriched were lariats small, four-amino-acid macrocycle followed short linear sequence that resembled natural Mcl-1 ligands. These "Heliats" (helical lariats) bound with tens nM affinity, inhibited interaction peptide ligand. Macrocyclization was found stabilize structures significantly contribute affinity potency. Yet, 2nd 3rd positions within permissible variation, so minimal macrocyclic motif,

Язык: Английский

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Bioinformatics approach for structure modeling, vaccine design, and molecular docking of Brucella candidate proteins BvrR, OMP25, and OMP31

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 25, 2024

Abstract Brucellosis is a zoonotic disease with significant economic and healthcare costs. Despite the eradication efforts, persists. Vaccines prevent in animals while antibiotics cure humans limitations. This study aims to design vaccines drugs for brucellosis humans, using protein modeling, epitope prediction, molecular docking of target proteins (BvrR, OMP25, OMP31). Tertiary structure models three were constructed assessed RMSD, TM-score, C-score, Z-score, ERRAT. The best selected from AlphaFold I-TASSER due their superior performance according CASP 12 – 15 chosen further analysis. motif analysis MotifFinder revealed two, five, five binding motifs, however, Motif Scan identified seven, six, eight Post-Translational Modification sites (PTMs) BvrR, OMP31 proteins, respectively. Dominant B cell epitopes predicted at (44–63, 85–93, 126–137, 193–205, 208–237), (26–46, 52–71, 98–114, 142–155, 183–200), (29–45, 58–82, 119–142, 177–198, 222–251) proteins. Additionally, cytotoxic T lymphocyte detected (173–181, 189–197, 202–210), (61–69, 91–99, 159–167, 181–189), (3–11, 24–32, 167–175, 216–224), helper displayed (39–53, 57–65, 150–158, 163–171), (79–87, 95–108, 115–123, 128–142, 189–197), (39–47, 109–123, 216–224, 245–253), respective protein. Furthermore, structure-based virtual screening ZINC DrugBank databases MOE program was followed by ADMET compounds database scores ranged (− 16.8744 − 15.1922), 16.0424 14.1645), 14.7566 13.3222) OMP31, These had good parameters no cytotoxicity, didn't meet Lipinski's rule criteria. Therefore, ZINC20 may fulfill pharmacokinetics could be considered lead molecules potentially inhibiting Brucella’s

Язык: Английский

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Revisiting Pyrimidine-Embedded Molecular Frameworks to Probe the Unexplored Chemical Space for Protein–Protein Interactions

Accounts of Chemical Research, Год журнала: 2024, Номер 57(22), С. 3254 - 3265

Опубликована: Окт. 31, 2024

ConspectusProtein–protein interactions (PPIs) are essential in numerous biological processes and diseases, making them attractive yet challenging drug targets. While many advances have been made traditional discovery, targeting PPIs has difficult due to a lack of specialized chemical libraries designed modulate these interactions. Current mainly focus on conventional target proteins like enzymes or receptors as substrate analogs rather than small-molecule modulators PPIs. These targets behave differently from Conventional druggable relatively small surfaces binding pockets that allowed be targeted with current libraries, but As result, there is an urgent need for innovative approach expand the space.To address this, we developed privileged substructure-based diversity-oriented synthesis (pDOS) strategy, aimed at creating maximal skeletal diversity explore broader biochemical space. Pyrimidine serves substructure our approach, which employs several strategies: (i) silver-catalyzed iodine-mediated tandem cyclizations generate pyrimidine-embedded polyheterocycles; (ii) diverse pairing strategies produce pyrimidodiazepine-containing polyheterocyclic skeletons enhanced scaffold saturation; (iii) transformation develop pyrimidine-fused medium-sized azacycles via chemoselective cleavages migrations N–N C–N bond; (iv) design peptidomimetics systematically mimic three pivotal protein secondary structures using pyrimidodiazepine-based scaffolds; (v) identification small-molecules allosterically inhibits interaction between human ACE2 receptor-binding domain (RBD) SARS-CoV-2 spike block viral entry into host cells.Through approaches, generated 39 distinct frameworks, demonstrating significant molecular validated by chemoinformatic analyses such Tanimoto similarity principal moment inertia (PMI) analysis. This extends pyrimidine beyond linear bicyclic forms, polyheterocycles 3D structural diversity. novel frameworks overcome limitation simpler scaffolds, offering promising tools modulating PPIs.Our pDOS highlights how structure-embedded polyheterocycles, particularly those based pyrimidine, can effectively previously undruggable strategy provides new direction allowing development molecules operate drug-like rules. In addition expanding space PPI modulation, enables creation scaffolds suited complex dynamic interfaces. innovation could significantly impact therapeutic development, solutions intractable By scope pyrimidine-based opened up possibilities advancing biology.This perspective demonstrates potential outlines structurally platform discovery facilitating exploration untapped spaces potentially transforming way

Язык: Английский

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The role of genomics and proteomics in drug discovery and its application in pharmacy

Deleted Journal, Год журнала: 2025, Номер 7(6)

Опубликована: Май 27, 2025

Язык: Английский

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Solubility-Aware Protein Binding Peptide Design Using AlphaFold

Biomedicines, Год журнала: 2022, Номер 10(7), С. 1626 - 1626

Опубликована: Июль 7, 2022

New protein-protein interactions (PPIs) are identified, but PPIs have different physicochemical properties compared with conventional targets, making it difficult to use small molecules. Peptides offer a new modality target PPIs, designing appropriate peptide sequences by computation is challenging. Recently, AlphaFold and RoseTTAFold made possible predict protein structures from amino acid ultra-high accuracy, enabling de novo design. We designed peptides likely PPI as the using "binder hallucination" protocol of AfDesign, design method AlphaFold. However, solubility tended be low. Therefore, we loss function indices for acids developed solubility-aware AfDesign binder hallucination protocol. The in increased weight function; moreover, they captured characteristics indices. Moreover, higher affinity than random or single residue substitution when evaluated docking binding affinity. Our approach shows that can bind interface while controlling solubility.

Язык: Английский

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Analysis of physicochemical properties of protein–protein interaction modulators suggests stronger alignment with the “rule of five”

RSC Medicinal Chemistry, Год журнала: 2021, Номер 12(10), С. 1731 - 1749

Опубликована: Янв. 1, 2021

The physicochemical properties of protein–protein interaction (PPI) modulators vary between those on the market, in clinical trials, and early drug discovery pipeline.

Язык: Английский

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First-in-Class Allosteric Inhibitors of DNMT3A Disrupt Protein–Protein Interactions and Induce Acute Myeloid Leukemia Cell Differentiation

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(15), С. 10554 - 10566

Опубликована: Июль 22, 2022

We previously identified two structurally related pyrazolone (compound 1) and pyridazine 2) allosteric inhibitors of DNMT3A through screening a small chemical library. Here, we show that these compounds bind disrupt protein–protein interactions (PPIs) at the tetramer interface. This disruption is observed with distinct partner proteins occurs even when complexes are acting on DNA, which better reflects cellular context. Compound 2 induces differentiation myeloid leukemia cell lines including cells mutated R882. To date, molecules targeting limited to competitive AdoMet or DNA display extreme toxicity. Our work first identify mechanism inhibition involving PPIs DNMT3A. Ongoing optimization 1 provides promising basis induce treatment diseases aberrant DNMT3A, such as acute leukemia.

Язык: Английский

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Identification of small-molecule protein–protein interaction inhibitors for NKG2D

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(18)

Опубликована: Апрель 25, 2023

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ+, and CD8+ T cell-mediated immune responses to environmental stressors such as viral or bacterial infections oxidative stress. However, aberrant signaling has also been associated with chronic inflammatory autoimmune diseases, thought be attractive target for intervention. Here, we describe comprehensive small-molecule hit identification strategy two distinct series of protein-protein interaction inhibitors NKG2D. Although the hits are chemically distinct, they share unique allosteric mechanism disrupting ligand binding by accessing cryptic pocket causing monomers dimer open apart twist relative one another. Leveraging suite biochemical cell-based assays coupled structure-based drug design, established tractable structure-activity relationships chemical successfully improved both potency physicochemical properties. Together, demonstrate it possible, albeit challenging, disrupt between multiple protein ligands single molecule through modulation dimer/ligand interface.

Язык: Английский

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