Aug 2026· The Scientist· Vol 8, pp. 204· 0 citations· 30 references
TL;DR
It is demonstrated that quadrant-based fragment docking provides an effective strategy for designing inhibitors targeting proteins with large binding cavities and provides promising lead compounds for the development of TIPE2 inhibitors.
Abstract
Chronic inflammation is closely associated with cancer progression through the promotion of angiogenesis and tumor-supportive signaling pathways. Tumor necrosis factor-α–induced protein 8-like 2 (TIPE2) regulates leukocyte polarization through phosphoinositide transport and represents a promising therapeutic target for solid tumors. However, the large hydrophobic cavity of TIPE2 presents a significant challenge for inhibitor design. In this work, a quadrant docking grid system was developed to enable fragment docking in defined regions of the binding cavity, facilitating fragment linking with minimal overlap and maximal spatial coverage. To our knowledge, this is the first application of a quadrant grid docking strategy for fragment-based inhibitor design. Fragments were screened using AutoDock Vina 1.2.3 and selected based on both binding affinity and predicted aqueous solubility. The highest-binding linked compounds, F1-F12 and F1-F13, exhibited binding affinities of −12.4 and −11.5 kcal mol−1, respectively. Rational modifications yielded compounds MF112 and MF113 with improved predicted ADME properties while maintaining strong binding affinities of −11.7 kcal mol−1. Molecular dynamics simulations demonstrated stable binding complexes over 5 ns trajectories, with RMSD stabilization after approximately 1–2 ns. These results demonstrate that quadrant-based fragment docking provides an effective strategy for designing inhibitors targeting proteins with large binding cavities and provides promising lead compounds for the development of TIPE2 inhibitors.
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
The integrated computational approach identified ZINC000000867238 as a potent and stable CCR5 inhibitor candidate, warranting further in vitro and in vivo validation as a potential HIV-1 entry blocker.
A. Sathish Kumar, Estari Mamidala· Journal of Receptor and Sign...· 0 citations
The identified compounds may serve as valuable starting points for further experimental validation and structural optimization toward the development of novel anticancer agents targeting TRIM33, and establishes a robust computational framework for developing TRIM33α-targeted therapies.
Yingying Jiang, Hongwei Gao, Siyuan Wang et al.· Genome Instability & Disease· 0 citations
Cancer continues to be a major global health burden, with receptor tyrosine kinases such as EGFR, ERBB2, and VEGFR-3 being critical therapeutic targets due to their central roles in tumor growth, survival, and angiogenesis. Current therapies, while effective in some contexts, face limitations including resistance, toxicity, and high cost, highlighting the need for novel multi-target approaches. In this study, we report the isolation and computational characterization of a novel defensin-like peptide (DEFL) from Datura stramonium (GenBank accession KT371458). The peptide sequence encoded 74 amino acids and displayed characteristic cysteine-stabilized motifs. Docking simulations revealed favorable binding scores toward EGFR (- 80.6 ± 10.6), ERBB2 (- 63.6 ± 7.4), and VEGFR-3 (- 50.5 ± 6.7), with interactions involving residues located within predicted receptor-binding regions. To further assess stability, 100 ns molecular dynamics simulations were performed. RMSD profiles confirmed stable complexes, with EGFR stabilizing around 0.6-0.8 nm, ERBB2 around 0.7-0.9 nm, and VEGFR-3 at a tighter 0.3-0.4 nm. Ligand RMSDs indicated moderate flexibility for ERBB2 (peaks up to 1.3 nm) but tighter stability for VEGFR-3 (0.3-0.5 nm). RMSF analyses revealed minimal fluctuations (< 0.3 nm) at binding sites, and radius of gyration values remained stable, indicating compact receptor-peptide complexes (EGFR: 3.45-3.75 nm; ERBB2: 2.95-3.20 nm; VEGFR-3: 1.92-1.98 nm). Hydrogen bond profiling and additional trajectory analyses (DCCM and PCA) supported overall system equilibration without major structural disruption during the simulations. The Datura stramonium defensin-like peptide indicating a stable and energetically favorable peptide-receptor interactions at the computational level. Overall, the simulations indicate persistent peptide-receptor association and stable structural behavior of the complexes at the computational level. However, molecular docking and molecular dynamics simulations do not demonstrate functional inhibition of EGFR, ERBB2, or VEGFR-3, nor do they confirm anticancer efficacy. Therefore, these results should be interpreted strictly as hypothesis-generating in silico predictions, and experimental validation, including peptide synthesis, receptor-binding assays, extracellular-domain competition assays, and cancer cell-based functional studies, will be required to confirm biological relevance.
Shehla Javaid, Zahid Mushtaq, A. Jamil et al.· Scientific Reports· 0 citations
Fragment-based diffusion modeling is an efficient and interpretable strategy for the discovery of computationally prioritized PD-L1 small-molecule candidate inhibitors and offers a promising framework for tackling challenging targets in cancer immunotherapy.
Jun Liu, Yuxing Yi, Xiaoyan Wu et al.· Molecular diversity· 0 citations
INTRODUCTION
MEK1 plays a critical role in cellular survival and proliferation. Its activity is tightly regulated, and its dysregulation may lead to various cancers. It is frequently targeted for therapeutic intervention. 1,4-Naphthoquinones, a natural compound class, have garnered increasing interest for their anticancer potential.
METHODS
A comprehensive library of 1,4-naphthoquinones was obtained from the PubChem database. This library was subjected to virtual screening using molecular docking against the allosteric site of MEK1 kinase. Selection was based on DOCK scores and pose similarity to the native inhibitor BBM. Ten compounds were selected and analyzed in detail for binding affinity, binding poses, and molecular interactions. Molecular dynamics (MD) simulation was performed for the top candidate.
RESULTS
The ten shortlisted compounds exhibited strong binding affinities for MEK1. Key residues involved in binding, including Asp-190, Asp-208, Phe-209, Met-219, and Lys-97, were consistently engaged by the shortlisted compounds and the native inhibitor. MD simulation of the top compound confirmed its stable binding. Pose overlay revealed that similar scaffolds showed comparable binding energies and interactions. ADMET predictions were considered in hit prioritization.
DISCUSSION
Early enrichment of true positives over decoys strongly supports the screening protocol. The common key residues shared between the naphthoquinones and the native inhibitor suggest a similar inhibitory mechanism. ADMET-based predictions led to the identification of the five most promising candidates.
CONCLUSION
This study proposed ten 1,4-naphthoquinones as potential allosteric inhibitors of MEK1. After integrating DOCK scores, binding energy, and ADMET risk, five compounds emerged as the most promising. These results provide a computational foundation for further testing.
M. Rehan· Current pharmaceutical desig...· 0 citations