Identification of indole-based natural compounds as inhibitors of PARP-1 against triple-negative breast cancer: a computational study

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(5), P. 2667 - 2680

Published: May 8, 2023

Triple-negative breast cancer (TNBC) is the most aggressive kind of known to mankind. It a heterogeneous disease that formed due missing estrogen, progesterone and human epidermal growth factor 2 receptors. Poly(ADP-ribose) polymerase-1 (PARP-1) protein helps in development TNBC by repairing cells, which proliferate spread metastatically. To determine potential PARP-1 inhibitors (PARPi), 0.2 million natural products from Universal Natural Product Database were screened using molecular docking six hit compounds selected based on their binding affinity towards PARP-1. The bio-availability drug-like properties these evaluated ADMET analysis. Molecular dynamics simulations conducted for complexes 200 ns examine structural stability dynamic behaviour further compared with complex talazoparib (TALA), an FDA-approved PARPi. Using MM/PBSA calculations, we conclude HIT-3 HIT-5 (-25.64 -23.14 kcal/mol, respectively) show stronger energies than TALA (-10.74 kcal/mol). Strong interactions observed between hotspot residues, Asp770, Ala880, Tyr889, Tyr896, Ala898, Asp899 Tyr907, existence various types non-covalent This research offers critical information about PARPi, could potentially be incorporated into treatment TNBC. Moreover, findings validated comparing them

Language: Английский

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Exploration of novel hydroxamate zinc binding group inhibitors against HDAC-1-3 enzymes by AI-based virtual screening: atomistic insights from steered molecular dynamics

Journal of Biomolecular Structure and Dynamics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 12

Published: March 8, 2024

Overexpression of histone deacetylase (HDAC) enzymes is linked to a wide variety illnesses, including malignancies and neurological disorders, which makes HDAC inhibitors potentially therapeutic. However, most lack subclass or isoform selectivity, can be dangerous. Featuring both enhanced selectivity toxicity profiles, slow-binding offer promising treatment options for disorders. Diseases like cardiac, neurodegenerative disorders diabetes are mainly associated with the HDAC1, HDAC2 HDAC3 enzymes. The AI-based virtual screening tool PyRMD implemented identify potential from ∼2 million compounds. Based on IC50 values, top 10 compounds were selected molecular docking. From docking ADMET study, top-ranked three dynamics (MD) simulations. Further, get more insights into binding/unbinding mechanism ligand, we have employed steered (SMD) This study assists in developing Amber force field parameters proteins sheds light discovery potent drug. Our suggests that hydroxamic acid derivative (i.e. referred as Comp-1, CHEMBL600072) inhibitor series HDAC-related diseases.

Language: Английский

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Computational Insights in Repurposing Cardiovascular Drug for Alzheimer's Disease: The Role of Aromatic Amino Acids in Stabilizing the Drug through π-π Stacking Interaction

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

HDAC2 represents a promising and visually striking epigenetic target to address Alzheimer's disease calculation suggests that π–π stacking interactions play major role in helping the ligand bind zinc binding domain of protein.

Language: Английский

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