Identification of BRD4 (BD1) Selective Inhibitors Based on Machine Learning, Molecular Docking and Molecular Dynamics Simulation

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(15)

Published: April 1, 2025

Abstract Bromodomain‐containing protein 4 (BRD4) is regarded as a promising therapeutic target for cancer and inflammation due to its crucial role in regulating transcription elongation gene expression. However, current pan‐BRD4 inhibitors have shown resistance dose‐limiting toxicity clinical trials, highlighting the need domain selective BRD4 inhibitors. To identify inhibitors, we constructed machine learning models with good predictive performance based on reported of first bromodomain (BD1) second (BD2). Then, optimal molecular docking were then employed screen compounds potential inhibitory activity from ZINC database. Afterward, three hit selected further evaluation through dynamics simulations. The results indicated that binding stabilized structure during 250 ns In comparison, these (BD2) did not exhibit same stabilizing effect (BD1), indicating their inhibition over This study demonstrates effectiveness learning, docking, simulation discovery offers novel insights into research

Language: Английский

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Targeting the epigenetic reader “BET” as a therapeutic strategy for cancer

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 140, P. 106833 - 106833

Published: Sept. 4, 2023

Language: Английский

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Uterine fibroids: current research on novel drug targets and innovative therapeutic strategies

Expert Opinion on Therapeutic Targets, Journal Year: 2024, Volume and Issue: 28(8), P. 669 - 687

Published: Aug. 2, 2024

Introduction Uterine fibroids, the most common nonmalignant tumors affecting female genital tract, are a significant medical challenge. This article focuses on recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy.

Language: Английский

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Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary consider the potential off-target toxicity associated with inhibition of four BET BD2 proteins. To date, no BRD4 domain selective inhibitor has reported. Based on our previous pan-BD2

Language: Английский

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Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12669 - 12669

Published: Aug. 11, 2023

The bromodomain and extra-terminal domain (BET) family inhibitors are small molecules that target the dysregulated epigenetic readers, BRD2, BRD3, BRD4 BRDT, at various transcription-related sites, including super-enhancers. BET currently under investigation both in pre-clinical cell culture tumor-bearing animal models, as well clinical trials. However, is case with other chemotherapeutic modalities, development of resistance likely to constrain therapeutic benefits this strategy. One tumor survival mechanism has been studied for decades autophagy. Although four different functions autophagy have identified literature (cytoprotective, cytotoxic, cytostatic non-protective), primarily cytoprotective cytotoxic forms appear function experimental models exposed (with some evidence form). This review provides an overview cytoprotective, response models. Our aim determine whether targeting or modulation could represent effective strategy enhance these modalities also potentially overcome inhibition.

Language: Английский

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BRD4 as a Therapeutic Target in Pulmonary Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(17), P. 13231 - 13231

Published: Aug. 25, 2023

Bromodomain and extra-terminal domain (BET) proteins are epigenetic modulators that regulate gene transcription through interacting with acetylated lysine residues of histone proteins. BET have multiple roles in regulating key cellular functions such as cell proliferation, differentiation, inflammation, oxidative redox balance, immune responses. As a result, been found to be actively involved broad range human lung diseases including acute asthma, pulmonary arterial hypertension, fibrosis, chronic obstructive disease (COPD). Due the identification specific small molecular inhibitors proteins, targeting these has become an area increasing interest. Emerging evidence demonstrated beneficial effects preclinical models various diseases. This is, general, largely related ability bind promoters genes critical for beyond. By modulating genes, integrated into pathogenesis progression. The intrinsic acetyltransferase activity bromodomain-containing protein 4 (BRD4) is particular interest, seems act independently its bromodomain binding activity, implication some contexts. In this review, we provide brief overview research on focus BRD4 several major diseases, underlying mechanisms, well findings using pharmaceutical different preclinically.

Language: Английский

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Computational Studies to Understand the Neuroprotective Mechanism of Action Basil Compounds

Molecules, Journal Year: 2023, Volume and Issue: 28(20), P. 7005 - 7005

Published: Oct. 10, 2023

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, pose a significant global health challenge, emphasizing the need for novel neuroprotective agents. Basil (Ocimum spp.) has been recognized its therapeutic potential, numerous studies have reported effects. In this manuscript, we present computational protocol to extricate underlying mechanism of action basil compounds in Molecular docking-based investigation chemical interactions between selected bioactive from key targets, including AChE, GSK3β, γ-secretase, sirtuin2. Our results demonstrate that compound myricerone caffeoyl ester possesses high affinity -10.01 -8.85 kcal/mol against GSK3β respectively, indicating their potential modulating various neurobiological processes. Additionally, molecular dynamics simulations were performed explore protein-ligand complexes' stability analyze bound compounds' dynamic behavior. This comprehensive enlightens putative mechanistic basis effects compounds, providing rationale use neurodegenerative disorders after further experimental validation.

Language: Английский

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Sifting Through the Noise: A Computational Pipeline for Accurate Prioritization of Protein-Protein Binding Candidates in High-Throughput Protein Libraries

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

Published: Jan. 23, 2024

Abstract Identifying the interactome for a protein of interest is challenging due to large number possible binders. High-throughput experimental approaches narrow down binding partners, but often include false positives. Furthermore, they provide no information about what region (e.g. epitope). We introduce novel computational pipeline based on an AlphaFold2 (AF) Competition Assay (AF-CBA) identify proteins that bind target from pull-down experiment, along with epitope. Our focus Extraterminal (ET) domain Bromo and (BET) proteins, we also nine additional systems show transferability other peptide-protein systems. describe series limitations methodology intrinsic deficiencies AF AF-CBA, help users scenarios where approach will be most useful. Given speed accuracy methodology, expect it generally applicable facilitate selection verification starting high-throughput libraries. Table Contents

Language: Английский

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Apoptosis and Autophagy: Therapeutic Implications in Cancer

International Journal of experimental research and review, Journal Year: 2024, Volume and Issue: 37, P. 36 - 60

Published: March 30, 2024

Despite the advances in medical field so far, cancer remains a global health priority even now. Considering drug resistance and failure of therapies to achieve complete eradication cells certain populations, developing molecules that induce programmed cell death or apoptosis has been focus research for several decades. Apoptosis evasion is one hallmarks cells, efforts continue annihilation through selective killing. On other hand, autophagy, mode degradation, considered double-edged sword. Recent studies show autophagy also can be manipulated selectively target based on tumor microenvironment cellular context. Studies an evolutionarily conserved process initiated during stress response enormous importance maintaining physiological balance. Most importantly, dynamic equilibrium between crucial homeostasis. Although ‘cell eating’ process, fate autophagic depends entirely nature extent crosstalk autophagy. This understanding immense significance when designing therapeutic interventions targeting Currently, are ongoing gain insights into role initiation, invasion, progression, angiogenesis, metastasis. review focuses two major mechanisms, context cancer, their crosstalk, both modes death.

Language: Английский

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A Computational Pipeline for Accurate Prioritization of Protein‐Protein Binding Candidates in High‐Throughput Protein Libraries

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(24)

Published: April 8, 2024

Identifying the interactome for a protein of interest is challenging due to large number possible binders. High-throughput experimental approaches narrow down binding partners but often include false positives. Furthermore, they provide no information about what region (e.g., epitope). We introduce novel computational pipeline based on an AlphaFold2 (AF) Competitive Binding Assay (AF-CBA) identify proteins that bind target from pull-down experiment and epitope. Our focus Extraterminal (ET) domain Bromo (BET) proteins, we also nine additional systems show transferability other peptide-protein systems. describe series limitations methodology intrinsic deficiencies AF AF-CBA help users scenarios where approach will be most useful. Given method's speed accuracy, anticipate its broad applicability epitope regions among potential partners, setting stage verification.

Language: Английский

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