Investigating the binding mechanism of AML inhibitors based on panobinostat with HDAC3 proteins using Gaussian accelerated molecular dynamics.

Class I histone deacetylases (HDACs) play a crucial role in the transformation and survival of myeloid and lymphoid malignancies, with HDAC1, 2, and 3 (Class I HDACs) being potential molecular targets for acute myelogenous leukemia (AML) treatment. Among them, HDAC3 depletion or inhibition significantly reduces proliferation and promotes differentiation in leukemia, with inhibitors like Panobinostat and compound 13a showing promise in suppressing its activity. In this study, we utilized Gaussian accelerated molecular dynamics (GaMD) simulations to compare the inhibitory potency of 13a and Panobinostat against HDAC3.

Exploring Hidden Dangers: Predicting Mycotoxin-like Toxicity and Mapping Toxicological Networks in Hepatocellular Carcinoma.

Mycotoxins are potent triggers of hepatocellular carcinoma (HCC) due to their intricate interplay with cellular macromolecules and signaling pathways. This study integrates machine learning and biomolecular analyses to elucidate the mechanisms underlying mycotoxin-induced hepatocarcinogenesis. Using a data set of 1767 mycotoxins and 1706 non-mycotoxin fungal metabolites, we evaluated 51 machine learning models.

Large Language Models as Tools for Molecular Toxicity Prediction: AI Insights into Cardiotoxicity.

The importance of drug toxicity assessment lies in ensuring the safety and efficacy of the pharmaceutical compounds. Predicting toxicity is crucial in drug development and risk assessment. This study compares the performance of GPT-4 and GPT-4o with traditional deep-learning and machine-learning models, WeaveGNN, MorganFP-MLP, SVC, and KNN, in predicting molecular toxicity, focusing on bone, neuro, and reproductive toxicity.

Discovery of TRPV4-Targeting Small Molecules with Anti-Influenza Effects Through Machine Learning and Experimental Validation.

Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel critical for maintaining intracellular Ca homeostasis and is essential in regulating immune responses, metabolic processes, and signal transduction. Recent studies have shown that TRPV4 activation enhances influenza A virus infection, promoting viral replication and transmission. However, there has been limited exploration of antiviral drugs targeting the TRPV4 channel.

Network Pharmacology and Bioinformatics Study of Six Medicinal Food Homologous Plants Against Colorectal Cancer.

Integrating network pharmacological analysis and bioinformatic techniques, this study systematically investigated the molecular mechanisms of six medicinal food homologous plants (, , , , , and ) against colorectal cancer. Through screening the TCMSP database, 303 active compounds and 453 drug targets were identified. By integrating differential expression gene analysis with WGCNA on the GSE41258 dataset from the GEO database, 49 potential therapeutic targets were identified.

Unveiling the Anti-Obesity Potential of Thunder God Vine: Network Pharmacology and Computational Insights into Celastrol-like Molecules.

Obesity, characterized by abnormal or excessive fat accumulation, has become a chronic degenerative health condition that poses significant threats to overall well-being. Pharmacological intervention stands at the forefront of strategies to combat this issue. Recent studies, notably by Umut Ozcan's team, have uncovered the remarkable potential of Celastrol, a small-molecule compound derived from the traditional Chinese herb thunder god vine (Tripterygium wilfordii) as an anti-obesity agent.

Using Gaussian accelerated molecular dynamics combined with Markov state models to explore the mechanism of action of new oral inhibitors on Complex I.

In this study, our focus was on investigating H-1,2,3-triazole derivative HP661 as a novel and highly efficient oral OXPHOS inhibitor, with its molecular-level inhibitory mechanism not yet fully understood. We selected the ND1, NDUFS2, and NDUFS7 subunits of Mitochondrial Complex I as the receptor proteins and established three systems for comparative analysis: protein-IACS-010759, protein-lead compound 10, and protein-HP661. Through extensive analysis involving 500 ns Gaussian molecular dynamics simulations, we gained insights into these systems.

Elucidating the structural basis of vitamin B derivatives as novel potent inhibitors of PTP1B: Insights from inhibitory mechanisms using Gaussian accelerated molecular dynamics (GaMD) and in vitro study.

Vitamin B is a group of biologically active cobalamin compounds. In this study, we investigated the inhibitory effects of methylcobalamin (MeCbl) and hydroxocobalamin acetate (OHCbl Acetate) on protein tyrosine phosphatase 1B (PTP1B). MeCbl and OHCbl Acetate exhibited an IC of approximately 58.

Building a Kokumi Database and Machine Learning-Based Prediction: A Systematic Computational Study on Kokumi Analysis.

Kokumi is a subtle sensation characterized by a sense of fullness, continuity, and thickness. Traditional methods of taste discovery and analysis, including those of kokumi, have been labor-intensive and costly, thus necessitating the emergence of computational methods as critical strategies in molecular taste analysis and prediction. In this study, we undertook a comprehensive analysis, prediction, and screening of the kokumi compounds.

Probing the mechanisms of hydrazide-based HDAC inhibitors binding to HDAC3 using Gaussian accelerated molecular dynamics (GaMD) simulations.

Histone deacetylases (HDACs) have emerged as promising targets for anticancer drug development. They regulate gene expression by removing acetyl groups from lysine residues on histone tails, leading to chromatin condensation. A hydrazide-based HDAC inhibitor, N-(4-(2-Propylhydrazine-1-carbonyl)benzyl)-1H-indole-2-carboxamide (11h), has been reported to exhibit significant antitumor activity.

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib.

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers.

Molecular mechanisms of metal ions in regulating the catalytic efficiency of D-psicose 3-epimerase revealed by multiple short molecular dynamic simulations and free energy predictions.

Communicated by Ramaswamy H. Sarma.