Biochemical and biophysical research communications · 2025
Exploring benzhydroxamic acid as a multi-target lead: Integrated strategies of network pharmacology, molecular docking, dynamic simulations, and MM/GBSA analysis for neuropathic pain therapy.
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Arjun Gokulan M, Narayanan J
Аннотация
INTRODUCTION: Neuropathic pain (NP), a debilitating condition affecting millions globally, remains challenging to treat effectively due to the limited efficacy and severe side effects of existing medications. Recent studies have highlighted the role of epigenetic and proteolytic mechanisms, including histone deacetylases (HDACs) and matrix metalloproteinases (MMPs), in NP pathophysiology.
MATERIALS & METHODS: From an initial pool of 17 compounds sourced via literature, seven derivatives were selected based on ADMET and toxicity profiles. Swiss Target Prediction and disease databases identified 291 compound targets and 13,648 NP-related genes, revealing 274 overlapping hub genes. Protein-protein interaction (PPI) analysis highlighted top targets such as SRC (score: 110), PTGS2 (score: 87), and MMP9 (score: 83).
RESULTS & DISCUSSION: Gene Ontology and KEGG enrichment showed strong associations with inflammatory response, chromatin modification, and PI3K-Akt signaling. Molecular docking revealed that benzhydroxamic acid had consistently favorable binding scores across key proteins (e.g., -5.508 kcal/mol with PTGS2, -5.483 kcal/mol with MMP9). Molecular dynamics simulations over 100 ns confirmed the stability of benzhydroxamic acid-PTGS2 complex, with RMSD stabilizing at ∼1.7 Å for the protein and ∼2.5 Å for the ligand. In contrast, higher ligand RMSD (∼9 Å) in the benzhydroxamic acid-MMP9 complex indicated less stability. Binding free energy calculations (MM-GBSA) showed that pregabalin-MMP9 had the most favorable ΔG (-46.915 kcal/mol), while benzhydroxamic acid-MMP9 also exhibited strong affinity (-39.990 kcal/mol). Normal Mode Analysis (NMA) revealed reduced conformational entropy, with benzhydroxamic acid-MMP9 showing -9.487 kcal mol-1 K-1 and pregabalin-MMP9 reaching -10.472 kcal mol-1 K-1.
CONCLUSION: Collectively, these results position benzhydroxamic acid as a promising candidate for NP therapy. Overall, this computational-based research provides a strong basis for the rational design of dual-target therapy for managing neuropathic pain with benzhydroxamic acid.
MATERIALS & METHODS: From an initial pool of 17 compounds sourced via literature, seven derivatives were selected based on ADMET and toxicity profiles. Swiss Target Prediction and disease databases identified 291 compound targets and 13,648 NP-related genes, revealing 274 overlapping hub genes. Protein-protein interaction (PPI) analysis highlighted top targets such as SRC (score: 110), PTGS2 (score: 87), and MMP9 (score: 83).
RESULTS & DISCUSSION: Gene Ontology and KEGG enrichment showed strong associations with inflammatory response, chromatin modification, and PI3K-Akt signaling. Molecular docking revealed that benzhydroxamic acid had consistently favorable binding scores across key proteins (e.g., -5.508 kcal/mol with PTGS2, -5.483 kcal/mol with MMP9). Molecular dynamics simulations over 100 ns confirmed the stability of benzhydroxamic acid-PTGS2 complex, with RMSD stabilizing at ∼1.7 Å for the protein and ∼2.5 Å for the ligand. In contrast, higher ligand RMSD (∼9 Å) in the benzhydroxamic acid-MMP9 complex indicated less stability. Binding free energy calculations (MM-GBSA) showed that pregabalin-MMP9 had the most favorable ΔG (-46.915 kcal/mol), while benzhydroxamic acid-MMP9 also exhibited strong affinity (-39.990 kcal/mol). Normal Mode Analysis (NMA) revealed reduced conformational entropy, with benzhydroxamic acid-MMP9 showing -9.487 kcal mol-1 K-1 and pregabalin-MMP9 reaching -10.472 kcal mol-1 K-1.
CONCLUSION: Collectively, these results position benzhydroxamic acid as a promising candidate for NP therapy. Overall, this computational-based research provides a strong basis for the rational design of dual-target therapy for managing neuropathic pain with benzhydroxamic acid.