Issue #3: Cytotoxicity, apoptosis, molecular docking, and molecular dynamics study of novel compounds of Sulfamide derivatives coupled with DHP scaffolds as potent inhibitors of the MCF-7, A549, SKOV-3, and EA. yh926 carcinoma cells.

Signal of the Day

Cytotoxicity, apoptosis, molecular docking, and molecular dynamics study of novel compounds of Sulfamide derivatives coupled with DHP scaffolds as potent inhibitors of the MCF-7, A549, SKOV-3, and EA. yh926 carcinoma cells.

A novel series of dihydropyridine-sulfonyl derivatives (AG-CHO and analogues A1-A7) were synthesized and structurally characterized. Molecular docking demonstrated favorable binding of these compounds to autophagy-associated and cancer-related targets, while molecular dynamics simulations confirmed A5 as the most stable ligand protein interactions. Functional assays in SKOV-3, MCF-7, A549, and EA.hy.926 cells using acridine orange staining and flow cytometry revealed significant autophagy induction. Among all tested compounds AG-CHO emerged as the most potent inducer of autophagy. Notably, derivatives such as A6 and A7 showed selective potency in endothelial cells, whereas A1, A5, and A7 were effective in A549 cells, indicating cell-specific activity. Collectively, this integrated computational and experimental study identifies A5 as the lead compound and highlights dihydropyridine-sulfonyl scaffolds as promising autophagy modulators and potential anticancer candidates for further preclinical development.

Why this matters: Enhances small-molecule or peptide docking accuracy for targeted drug discovery.

Also Worth Reading

Meeko: Molecule Parametrization and Software Interoperability for Docking and Beyond.

Molecule parametrization is an essential requirement to guarantee the accuracy of docking calculations. Parametrization includes a proper perception of chemical properties such as bonds, formal charges and protonation states. This includes large biological macromolecules, such as proteins and nucleic acids, and small molecules, such as ligands and cofactors. The structures of proteins and nucleic acids are challenging due to omission of several atoms from the structural model, and from the lack of connectivity and bond order information in the PDB and mmCIF file formats. For small molecules, the very large chemical diversity poses challenges for both validating correctness and providing accurate parameters. These challenges affect various modeling approaches like molecular docking and molecular dynamics. Moreover, several specialized methods (particularly in molecular docking) leverage specific chemical properties to add custom potentials, pseudoatoms, or manipulate atomic connectivity. To address these challenges, we developed Meeko, a molecular parametrization Python package that leverages the widely used RDKit cheminformatics library for a chemically accurate description of the molecular representation. Small molecules are modeled as single RDKit molecules, and biological macromolecules as multiple RDKit molecules, one for each residue. Meeko is highly customizable and designed to be easily scriptable for high-throughput processing, replacing MGLTools for receptor and ligand preparation.

From sweetener to risk factor: Network toxicology, molecular docking and molecular dynamics reveal the mechanism of aspartame in promoting coronary heart disease.

Aspartame, a widely used non-nutritive sweetener, has been epidemiologically linked to coronary heart disease (CHD), although the underlying mechanisms remain unclear. This study employed an integrative computational strategy combining network toxicology, molecular docking, and molecular dynamics to decode aspartame’s CHD-promoting mechanisms. Initially, the toxicity profile of aspartame was predicted using ProTox 3.0 and ADMETlab 3.0, which highlighted significant cardiotoxicity. Through multi-source target screening of aspartame (PharmMapper, SEA, etc.) and CHD (GeneCards, OMIM), 216 shared targets were identified. Protein-protein interaction network analysis revealed 10 hub targets (INS, PPARGC1A, TNF, AKT1, IL6, MMP9, IGF1, PTGS2, SIRT1, PPARG). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed significant enrichment in lipid metabolism, inflammatory responses, insulin resistance, and atherosclerosis-related pathways. Molecular docking and molecular dynamics simulations (MDS) demonstrated high-affinity binding of aspartame to three core targets (PTGS2, TNF, and PPARGC1A), with a binding energy ≤ -7.0 kcal/mol, and confirmed high binding stability. This study reveals that aspartame may promote the pathogenesis of CHD by disrupting cardiovascular homeostasis through multi-target interactions, including inflammatory response, metabolic dysregulation, and vascular remodeling. These findings provide molecular evidence for re-evaluating the safety profile of aspartame and establish a computational framework to guide experimental validation and preventive strategies.

Research & AI Updates

• Largest protein classification in history finds 700,000 unknown structures - Earth.com — Largest protein classification in history finds 700,000 unknown structures    Earth.com.
• Structural findings reveal how distinct GPCR ligands create different levels of activation | Newswise - Newswise — Structural findings reveal how distinct GPCR ligands create different levels of activation | Newswise    Newswise.
• Kolmogorov-Arnold networks bridge AI and scientific discovery by increasing interpretability - Phys.org — Kolmogorov-Arnold networks bridge AI and scientific discovery by increasing interpretability    Phys.org.
• Bets on Generative AI to Redefine Drug Discovery——IntelliGenAI and their foundation model approach - Pandaily — Bets on Generative AI to Redefine Drug Discovery——IntelliGenAI and their foundation model approach    Pandaily.
• A novel DCSTAMP antagonist impedes preosteoclast fusion via modulation of RAP1B–RAC1-mediated cytoskeletal remodeling - Nature — A novel DCSTAMP antagonist impedes preosteoclast fusion via modulation of RAP1B–RAC1-mediated cytoskeletal remodeling    Nature.

From the Industry

• Layoff Tracker: Voyager Loses 30 Employees After Novartis Prunes Deal - BioSpace — Layoff Tracker: Voyager Loses 30 Employees After Novartis Prunes Deal    BioSpace.
• Galux, Boehringer Ingelheim to Jointly Explore AI in Precision Protein Design - Contract Pharma — Galux, Boehringer Ingelheim to Jointly Explore AI in Precision Protein Design    Contract Pharma.
• Profluent Bio Partners with Ensoma for AI-Designed Base Editors in Stem Cell Therapies - SynBioBeta — Profluent Bio Partners with Ensoma for AI-Designed Base Editors in Stem Cell Therapies    SynBioBeta.
• Lindus Health, Quotient Sciences Partner to Accelerate Drug Development to Clinical Trials - Contract Pharma — Lindus Health, Quotient Sciences Partner to Accelerate Drug Development to Clinical Trials    Contract Pharma.
• Europe Protein Engineering Market Size & Share, 2033 - Market Data Forecast — Europe Protein Engineering Market Size & Share, 2033    Market Data Forecast.

Quick Reads

Enzyme Engineering Database (EnzEngDB): a platform for sharing and interpreting sequence-function relationships across protein engineering campaigns.

The discovery and engineering of new enzymes is important across the bioeconomy, with diverse applications from foods to pharmaceuticals, sensors to agriculture. Read more →

Multi-target exploration of newly synthesized pyrazoline-quinoline derivatives via in vitro screening, QSAR, molecular docking, MD simulations, and DFT analysis.

The development of multifunctional therapeutic agents remains a promising strategy in modern drug discovery, particularly for diseases associated with oxidative stress, bacterial infections, and cancer progression. Read more →

UPLC-Q-TOF/MS-based Spectrum-effect Correlation Combined with Chemometrics and Molecular Docking for Quality Assessment and Screening of Bioactive Components with Hemostatic, Antinociceptive, and Anti-Inflammatory Activities in Liparis nervosa.

Ethnopharmacological relevance Liparis nervosa (LN) occurs in Southwest China and is traditionally used as a hemostatic and detoxifying agent; however, the pharmacodynamic basis for its medicinal properties is unclear; this impedes the quality standardization and clinical application of this herb. Read more →

Exploring the Mechanism of Platycladi Cacumen in Intervening Androgenetic Alopecia Based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation

Abstract As a traditional hair-growth-promoting herb, Platycladi Cacumen(PC) has a long history of folk application in the field of hair loss improvement. Read more →

A hardware demonstration of a universal programmable RRAM-based probabilistic computer for molecular docking.

Molecular docking is a critical computational strategy in drug discovery, but the diversity of biomolecular structures and flexible binding conformations create an enormous search space that challenges conventional computing. Read more →

Structure-Aware Antibody Design with Affinity-Optimized Inverse Folding

Motivation: The clinical efficacy of antibody therapeutics critically depends on high-affinity target engagement, yet laboratory affinity-maturation campaigns are slow and costly. Read more →

Pipeline Tip

Use Snakemake for reproducible end-to-end protein design workflows.

Resources & Tools

• Dataset: PDB-REDO - Optimized protein structure database with refined models.
• Dataset: Protein Data Bank (PDB) - The single global archive for macromolecular structure data.
• Tool: FunFOLD5 - Automated system for protein ligand-binding site prediction and function annotation. View all tools →
• Tool: MultiFOLD/IntFOLD - High-performance protein structure prediction and quality assessment server. View all tools →
• Event: Structural Biology Events (Open)
• Event: Protein Design Hub (LinkedIn Group) (Ongoing)
• Job: Mercor hiring PhD Scientist AI Bioinformatics in Greater Montreal Metropolitan Area - LinkedIn at Bioinformatics Careers
• Job: Programme Manager – Human Genomics and Translational Data (HGTD) - LinkedIn at Bioinformatics Careers

Deep learning is not a magic wand, but a powerful lens for structural biology. — Recep Adiyaman