Aug 2026· Current Chemical Biology· Vol 20· 0 citations
TL;DR
The identification of marine-derived compounds addresses the need to overcome resistance to single-checkpoint immunotherapy and are regarded as earlystage lead scaffolds requiring structural optimization rather than hits with acceptable overall safety profiles.
Abstract
Inhibiting overexpressed key immunoregulatory proteins, programmed
death-ligand 1 (PD-L1) and V-domain immunoglobulin suppressor of T cell activation (VISTA),
represents a critical strategy for restoring antitumor immunity. These proteins are upregulated under
hypoxic conditions, leading to immune evasion and drug resistance to monotherapy.
In this study, a comprehensive computational workflow, including structure-based pharmacophore
screening and validation, molecular docking, predictive toxicity profiling, and molecular
dynamics (MD) simulations, was used to explore a marine database for compounds that bind
PD-L1 and VISTA simultaneously.
The retrospective pharmacophore validation of known actives and decoys confirmed the
discriminatory reliability of both PD-L1 and VISTA models. From the common pharmacophore
alignment of PD-L1 and VISTA models, 235 marine compounds exhibited RMSD values <2.0 Å.
Based on the molecular docking screening of these common hits, CMNPD14606, CMNPD20027,
and CMNPD20697 were found to have higher affinities than the reference P17 and S8. Additionally,
these hits demonstrated favorable physicochemical profiles; however, the in-silico toxicity profiling
revealed modest-to-high genotoxicity and mutagenicity liabilities for all three compounds,
which represent key safety limitations. The MD simulations, performed in triplicate for up to 100
ns, confirmed MD stability across independent replicates.
The identification of marine-derived compounds addresses the need to overcome resistance
to single-checkpoint immunotherapy. Accordingly, these compounds are regarded as earlystage
lead scaffolds requiring structural optimization rather than hits with acceptable overall safety
profiles.
These results suggest the development of dual-targeting PD-L1/VISTA compounds
that warrant lead optimization to mitigate toxicity risks before further experimental investigation.
PE-1 demonstrates dual-target inhibitory activity against the PD-1/PD-L1 immune checkpoint and EZH2, underscoring its potential as a lead compound for the development of next-generation bifunctional anticancer agents.
B. Guan, Binbin Cheng, Hongqiao Li· Frontiers in Immunology· 0 citations
INTRODUCTION/OBJECTIVE
The KRAS G12D mutation is a significant oncogenic factor that promotes cell proliferation and tumor development, particularly in pancreatic cancer. Inhibiting the mutated form of the KRAS protein is a critical strategy in cancer treatment. While molecules like MRTX1133 show promise, the limited efficacy and safety of current treatment options highlight the need to discover new and safer therapeutic candidates.
METHODS
Approximately 1000 plant-derived bioactive compounds downloaded from the literature and Dr. Duke's database were filtered according to Lipinski's Rules and pharmacokinetic properties to create a set of 425 candidate molecules. Geometry optimization and QSAR parameters were calculated using Spartan software, and molecular docking and binding affinities were calculated using AutoDock Vina. MRTX1133 was used as a reference in the evaluations. Protein-ligand interaction maps were generated, and key interaction residues were identified using BIOVIA Discovery Studio. Molecular dynamics simulations of 200 ns were performed using Schrödinger-Desmond for the six compounds with the best binding affinities, and MMGBSA binding free energy calculations were performed.
RESULTS
The results showed that Isochlorogenic acid, Coniferin, Neochlorogenic acid, Cryptochlorogenic acid, Gamma-L-glutamyl-L-phenylalanine, and Chlorogenic acid demonstrated good bonding affinity to KRAS G12D with -11.0, -9.8, -9.5, -9.1, -9, and -8.9 Kcal.mol-1, respectively, compared to MRTX1133 (-8.3 Kcal.mol-1), exhibiting favorable physicochemical profiles and revealing their potential as KRAS G12D inhibitors. Based on bonding scores and QSAR data, four of the six selected molecules (Coniferin, Gamma-Lglutamyl- L-phenylalanine, Isochlorogenic acid, and Neochlorogenic acid) formed stable protein-ligand complexes with mean RMSD values < 2.5 Å during 200 ns MD simulations. MMGBSA analysis confirmed the binding free energies, and the compound giving the strongest interaction was determined to be Coniferin with ΔG_bind = -72.53 ± 5.24 Kcal.mol-1. Superior docking scores and stable MD trajectories demonstrate that the selected plant-derived compounds, especially Coniferin, effectively interact with the KRAS G12D binding pocket via suitable hydrophobic and hydrogen-bond contacts. These findings suggest that natural compounds can provide structurally diverse and potentially safer alternatives compared to synthetic inhibitors; however, experimental validation is necessary to confirm their inhibitory potential and selectivity.
DISCUSSION
According to the MMGBSA results, these compounds have suitable binding free energy values comparable to the reference, with Coniferin as the strongest plant-derived candidate with ΔGbind = -72.53 ± 5.24 Kcal/mol-.
CONCLUSION
As a result of this in silico study, coniferin, neochlorogenic acid, and chlorogenic acid have been identified as potential precursor molecules for KRAS G12D inhibition. Isochlorogenic acid was excluded due to its dynamic instability. These plant-derived compounds require further experimental validation as potential anticancer agents targeting KRAS G12D mutations.
Ebru Okutan, Serra Özışık, V. Atalay· Current pharmaceutical desig...· 0 citations
Mangostanol and 9-hydroxycalabaxanthone will be prioritized for in vitro/in vivo testing, underscoring the importance of a stepwise, structure-based approach to identify plant-based natural compounds targeting XIAP-BIR3.
S. Hodijah, Agus Kartono, Zahra Silmi Muscifah et al.· Indonesian Journal of Chemis...· 0 citations
Non-small-cell lung cancer (NSCLC) remains the leading cause of lung cancer–related mortality, largely driven by aberrant activation of the epidermal growth factor receptor (EGFR). Despite the clinical success of EGFR tyrosine kinase inhibitors (TKIs), intrinsic and acquired resistance, coupled with safety concerns, highlight the need for novel, safer inhibitors. Natural products represent an underexplored source of structurally diverse bioactive compounds with favorable biocompatibility. In this study, a comprehensive in silico approach is used to evaluate phytochemicals from Adenium obesum as potential candidate EGFR-targeting compound. Initially, sixteen phytochemicals were first assessed for predicted antineoplastic activity using PASS. High-scoring molecules were docked against the EGFR kinase domain (PDB ID: 1M17), besides performed detailed protein–ligand interaction analysis, drug-likeness and ADMET profiling, toxicity prediction and 100-ns molecular dynamics (MD) simulations. PASS-based bioactivity prediction revealed strong anticancer potential among the sixteen screened compounds, with consistently high antineoplastic and antiproliferative activity probabilities (Pa > 0.79) and low inactivity scores, supporting their selection for subsequent docking, ADMET, and molecular dynamics analyses. Next, several phytochemicals exhibited strong docking affinities, with Cardenolide achieving the highest binding score (–9.9 kcal/mol) and forming stable interactions with key catalytic residues. A 100-ns MD simulation confirmed the structural stability, persistent binding, and dynamic integrity of the EGFR–Cardenolide complex under physiological conditions. Importantly, interaction mapping revealed that Cardenolide engages conserved and functionally critical regions of the EGFR kinase domain associated with catalytic activity and structural stability, supporting its mechanistic relevance as an ATP-competitive scaffold. Additionally, predicted pharmacokinetic and toxicity profiles further supported Cardenolide’s suitability as a drug-like candidate. Collectively, these results identify Cardenolide as a computationally prioritized candidate with favorable predicted EGFR-binding characteristics, structural stability, and physicochemical and toxicity profiles. However, as the present study is based entirely on computational analyses, these findings should be considered hypothesis-generating and do not establish EGFR inhibitory activity or therapeutic efficacy. Experimental validation, including biochemical kinase inhibition and cellular assays, is therefore required to determine the actual EGFR inhibitory potential and anticancer activity of Cardenolide. Nevertheless, the findings provide a rational basis for prioritizing Cardenolide for further experimental investigation and illustrate the potential of Adenium obesum phytochemicals as a source of candidate EGFR-targeting compounds for future NSCLC drug discovery.
Md. Naziur Rahman, Abu Yousuf Hossin, S. Talukder et al.· PLoS ONE· 0 citations
The findings from molecular docking, 500-ns molecular dynamics simulations, MM-GBSA calculations, and alanine scanning analyses collectively corroborate a stable binding mode of BTB11556 within the MPO active site, support further investigation of BTB11556 as a candidate compound associated with MPO-targeted therapeutic strategies.
Maysoon Raed Alnajdawi, H. Wahab, Belal Alnajjar et al.· Journal of Computer-Aided Mo...· 0 citations
Findings establish coumarin-derived scaffolds as promising starting points for the development of next-generation CDK4-targeted therapeutics and provide a strong computational foundation for future experimental validation in NSCLC.
N. M. Arulmozhi, Thiyagarajan G· Applied Biochemistry and Bio...· 0 citations
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