Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Янв. 27, 2023

After over two years of living with Covid-19 and hundreds million cases worldwide there is still an unmet need to find proper treatments for the novel coronavirus, due also rapid mutation its genome. In this context, a drug repositioning study has been performed, using in silico tools targeting Delta Spike protein/ACE2 interface. To aim, it virtually screened library composed by 4388 approved drugs through deep learning-based QSAR model identify protein-protein interactions modulators molecular docking against receptor binding domain (RBD). Binding energies predicted complexes were calculated Molecular Mechanics/Generalized Born Surface Area from dynamics simulations. Four out top twenty ranking compounds showed stable modes on RBD evaluated their effectiveness Omicron. Among them antihistaminic drug, fexofenadine, revealed very low energy, complex, interesting RBD. Several found exhibit direct antiviral activity SARS-CoV-2 vitro, mechanisms action debated. This not only highlights potential our computational methodology screening variant-specific drugs, but represents further tool investigating properties selected drugs.

Язык: Английский

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Discovery of Ligands for TRIM58, a Novel Tissue-Selective E3 Ligase

ACS Medicinal Chemistry Letters, Год журнала: 2023, Номер 14(12), С. 1631 - 1639

Опубликована: Ноя. 13, 2023

Redirecting E3 ligases to neo-substrates, leading their proteasomal disassembly, known as targeted protein degradation (TPD), has emerged a promising alternative traditional, occupancy-driven pharmacology. Although the field expanded tremendously over past years, choice of remains limited, with an almost exclusive focus on CRBN and VHL. Here, we report discovery novel ligands PRY-SPRY domain TRIM58, RING ligase that is specifically expressed in erythroid precursor cells. A DSF screen, followed by validation using additional biophysical methods, led identification TRIM58 ligand TRIM-473. basic SAR around chemotype was established utilizing competitive binding assay employing short FP peptide probe derived from endogenous substrate. The X-ray co-crystal structure complex TRIM-473 gave insights into mode potential exit vectors for bifunctional degrader design.

Язык: Английский

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Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1550 - 1550

Опубликована: Янв. 28, 2022

Protein–protein interactions (PPIs) outnumber proteins and are crucial to many fundamental processes; in consequence, PPIs associated with several pathological conditions including neurodegeneration modulating them by drugs constitutes a potentially major class of therapy. Classically, however, the discovery small molecules for use as entails targeting individual rather than PPIs. This is largely because discovering modulate has been seen extremely challenging. Here, we review difficulties limitations strategies discover that target directly or indirectly, taking examples disordered involved neurodegenerative diseases.

Язык: Английский

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Structure-based assessment and druggability classification of protein–protein interaction sites

Scientific Reports, Год журнала: 2022, Номер 12(1)

Опубликована: Май 13, 2022

Abstract The featureless interface formed by protein–protein interactions (PPIs) is notorious for being considered a difficult and poorly druggable target. However, recent advances have shown PPIs to be druggable, with the discovery of potent inhibitors stabilizers, some which are currently clinically tested approved medical use. In this study, we assess druggability 12 commonly targeted using computational tool, SiteMap. After evaluating 320 crystal structures, find that PPI binding sites wide range scores. This can attributed unique structural physiochemical features influence their ligand concomitantly, predictions. We then use these propose specific classification system suitable assessing targets based on scores measured binding-affinity. Interestingly, was able distinguish between different correctly categorize them into four classes (i.e. very moderately difficult). also studied effects protein flexibility computed found conformational changes accompanying in ligand-bound structures result higher due more favorable features. Finally, drug-likeness many published where it vast majority 221 ligands here, including orally tested/marketed drugs, violate acceptable limits compound size hydrophobicity parameters. outcome, combined lack correlation observed drug-likeness, reinforces need redefine drugs. work proposes PPI-specific scheme will assist researchers identifying interface.

Язык: Английский

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SiteRadar: Utilizing Graph Machine Learning for Precise Mapping of Protein–Ligand-Binding Sites

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(4), С. 1124 - 1132

Опубликована: Фев. 6, 2023

Identifying ligand-binding sites on the protein surface is a crucial step in structure-based drug design. Although multiple techniques have been proposed, including those using machine learning algorithms, existing solutions do not provide significant advantages over nonmachine approaches and there still big room for improvement. The low ability to identify protein-ligand-binding makes available inapplicable automated Here, we present SiteRadar, new algorithm mapping cavities that are likely bind small-molecule ligand. SiteRadar shows higher accuracy binding site identification compared with FPocket PUResNet. demonstrates an detect up 74% of true according top N + 2 metric usually covers approximately 80% ligand atoms. Therefore, can be regarded as promising solution implementation into algorithms

Язык: Английский

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Design of Cyclic Peptides Targeting Protein–Protein Interactions Using AlphaFold

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(17), С. 13257 - 13257

Опубликована: Авг. 26, 2023

More than 930,000 protein-protein interactions (PPIs) have been identified in recent years, but their physicochemical properties differ from conventional drug targets, complicating the use of small molecules as modalities. Cyclic peptides are a promising modality for targeting PPIs, it is difficult to predict structure target protein-cyclic peptide complex or design cyclic sequence that binds protein using computational methods. Recently, AlphaFold with offset has enabled predicting peptides, thereby enabling de novo designs. We developed enable structural prediction proteins and complexes found AlphaFold2 can structures high accuracy. also applied binder hallucination protocol AfDesign, method AlphaFold, we could predicted local-distance difference test lower separated binding energy per unit interface area native MDM2/p53 structure. Furthermore, was 12 other protein-peptide one complex. Our approach shows possible putative sequences PPI.

Язык: Английский

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Targeting Protein–Protein Interfaces with Peptides: The Contribution of Chemical Combinatorial Peptide Library Approaches

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(9), С. 7842 - 7842

Опубликована: Апрель 25, 2023

Protein-protein interfaces play fundamental roles in the molecular mechanisms underlying pathophysiological pathways and are important targets for design of compounds therapeutic interest. However, identification binding sites on protein surfaces development modulators protein-protein interactions still represent a major challenge due to their highly dynamic extensive interfacial areas. Over years, multiple strategies including structural, computational, combinatorial approaches have been developed characterize PPI date, several successful examples small molecules, antibodies, peptides, aptamers able modulate these determined. Notably, peptides particularly useful tool inhibiting PPIs exquisite potency, specificity, selectivity. Here, after an overview commonly used identify them, we describe evaluate impact chemical peptide libraries medicinal chemistry with special focus results achieved through recent applications this methodology. Finally, also discuss role that methodology can framework opportunities, challenges application new predictive based artificial intelligence is generating structural biology.

Язык: Английский

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A dynamical view of protein-protein complexes: Studies by molecular dynamics simulations

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Окт. 6, 2022

Protein-protein interactions are at the basis of many protein functions, and knowledge 3D structures protein-protein complexes provides structural, mechanical dynamical pieces information essential to understand these functions. interfaces can be seen as stable, organized regions where residues from different partners form non-covalent that responsible for interaction specificity strength. They commonly described a peripheral region, whose role is protect core region concentrates most contributing interactions, solvent. To get insights into dynamics complexes, we carried out all-atom molecular simulations in explicit solvent on eight functional class interface size by taking account bound unbound forms. On one hand, characterized structural changes upon binding proteins, other hand extensively analyzed waters involved binding. Based our analysis, 6 cases 8, rearranged during simulation time, stable long-lived substates with alternative residue-residue contacts. These rearrangements not restricted side-chain fluctuations periphery but also affect interface. Finally, analysis pointed importance take their estimation

Язык: Английский

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Mapping the binding sites of challenging drug targets

Current Opinion in Structural Biology, Год журнала: 2022, Номер 75, С. 102396 - 102396

Опубликована: Май 27, 2022

Язык: Английский

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Targeting cryptic-orthosteric site of PD-L1 for inhibitor identification using structure-guided approach

Archives of Biochemistry and Biophysics, Год журнала: 2021, Номер 713, С. 109059 - 109059

Опубликована: Окт. 18, 2021

Язык: Английский

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