Jul 2026· International Journal of Molecular Sciences· Vol 27, pp. 6821· 0 citations· 99 references
Medicine
TL;DR
This study combines ligand- and structure-based in silico strategies to predict the inhibitory activity of natural flavonoids on the Polo-Like Kinase-1 (PLK-1) enzyme as candidate anticancer agents, offering a robust methodological framework for proposing candidates with a higher probability of success in subsequent stages of experimental validation, reducing time and costs in the early stages of drug development.
Abstract
This study combines ligand- and structure-based in silico strategies to predict the inhibitory activity of natural flavonoids on the Polo-Like Kinase-1 (PLK-1) enzyme as candidate anticancer agents. This enzyme participates in mitosis and is overexpressed in cancer cells. Furthermore, it has been shown to have important implications for tumor metastasis, and its inhibitors are attractive starting points for drug development. First, classification models are developed using linear discriminant analysis and a multilayer perceptron neural network. Models with accuracy greater than 80%, validated using standard statistical performance metrics and applicability domain, are used for virtual screening identifying four compounds as potential antitumor drugs. Subsequently, the identified compounds are evaluated using a molecular docking methodology to verify their binding mode and interactions with the catalytic domain of PLK-1. Finally, the integration of molecular dynamics simulations, at 300 ns, with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) thermodynamic calculations demonstrates that the hydroxylation pattern of ring B in the flavonol scaffold is the fundamental chemical-structural determinant of electrostatic interactions and the architecture of water-mediated networks. Among the evaluated flavonoids, myricetin showed the most favorable overall computational profile, including the highest virtual-screening score and the most favorable mean MM/GBSA estimate, supporting its prioritization for experimental evaluation as a potential PLK-1 inhibitor. The integration of these approaches offers a robust methodological framework for proposing candidates with a higher probability of success, in subsequent stages of experimental validation, reducing time and costs in the early stages of drug development.
Findings highlight Withaferin A as a promising natural inhibitor of UBE2J1 and provide a foundation for future experimental validation aimed at developing targeted therapies against ovarian cancer.
Zujaja Rehman, Ejaz Rasul, Wisha Asif et al.· In Silico Pharmacology· 0 citations
It is suggested that amentoflavone has potential as a natural lead compound for further optimization and development of ERα-targeted therapies in ER-positive breast cancer.
D. S. F. Ramadhan, Nurisyah Nurisyah, Asyhari Asyikin et al.· Indonesian Journal of Chemis...· 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
Acute myeloid leukemia is a type of leukemia caused by the disruption of the maturity of the hematopoiesis process at the myeloid lineage. The cause is a mutation in FMS-like tyrosine kinase 3 (FLT3) that triggers unregulated proliferation and differentiation signaling, so it can be used as a target receptor in its treatment. This study aims to find flavonoid compounds as potential compounds for FLT3 inhibitors. The method in this study uses a similarity search to isoliquiritigenin to search for flavonoids and then uses virtual screening techniques and molecular docking of FLT3 as well as predictions of its bioavailability and toxicity properties. This study resulted in 60 ligands from similarity search results. After conducting virtual screening, molecular docking, and prediction of bioavailability, and toxicity, 13 test ligands were found that have the potential to be drug candidates. This research concludes that sophoradin has a bond-free energy (∆G) of -9,697 kcal/mol which is the ligand as the strongest bonding in this research. The results are potential for further research as FLT3 inhibitors as candidates for the treatment of acute myeloid leukemia.
Wildan Aulia Noorsy, P. A. Kurniatin, U. M. S. Purwanto· Current Biochemistry· 0 citations
The current study focuses on developing a Quantitative Structure-Activity Relationship (QSAR) model for novel chrysin-benzimidazole derivatives as possible anti-cancer drugs for hepatocellular carcinoma (HepG2 cell line). The biological activity of 21 substances was measured using IC₅₀ values, which were then converted to pIC₅₀ for better statistical analysis. Molecular structures were optimized with the semi-empirical PM3 method, and ChemOffice software was used to calculate several physicochemical characteristics. Multiple linear regression analysis was used to find relationships between molecular characteristics and biological activity. The created QSAR models revealed a strong link between structural features and anticancer efficacy, emphasizing the significance of descriptors such as molar refractivity, partition coefficient, and related factors. The validated model demonstrated satisfactory prediction ability on both the training and test sets. This study sheds light on the structural prerequisites for anticancer action, which may aid in the rational development of more effective benzimidazole-based medicinal medicines.
Arun Kumar Rai, Keerti Sahu, Megha Chouhan et al.· World Journal of Current Med...· 0 citations
Aurora A kinase overexpression has been implicated in ovarian cancer progression, highlighting its potential as a therapeutic target. In this study, we performed structure-based virtual screening of our proprietary natural product database, identifying hinokiflavone (HNK) as a novel Aurora A inhibitor. Kinase profiling assays revealed that HNK exhibits multi-target inhibitory activity, with preferential potency against Aurora A and B. We developed the first efficient total synthesis of HNK derivatives featuring a key Chan-Lam coupling reaction. Based on the different positions of methoxy and hydroxyl groups in the structure of HNK and its derivatives, we also compared their molecular docking simulation and molecular dynamics simulation, and found that as the number of hydroxyl groups increased, the activity of inhibiting Aurora A gradually increased. The retention of hydroxyl groups at specific positions plays a crucial role in the activity of HNK. The aforementioned research provides a preliminary theoretical foundation for a subsequent structural modification.
Ke Wang, Guan-Yu Chen, Pei-Yi Chu et al.· European journal of medicina...· 0 citations
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