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Background <p>Renal cell carcinoma (RCC) represents a therapeutic challenge due to aberrant angiogenesis and oxidative stress pathways, and more off-site target drugs. Current VEGFR-2 inhibitors like Tyrosine kinase inhibitors (TKIs) demonstrate limited efficacy and significant side effects, lacking selectivity, necessitating novel multi-targeted approaches. Peptide-drug conjugates offer promising avenues for enhanced specificity and reduced toxicity in cancer therapeutics. Over the past decades, computational design has given fast and more reliable results.</p> Objective <p>To design, synthesize, and evaluate novel peptide-(D)-tetrahydroisoquinoline (THIQ) conjugates targeting VEGFR-2 signalling and oxidative stress pathways in RCC through integrated computational tools and experimental approaches.</p> Methods <p>Five hundred peptide-THIQ conjugates were rationally designed and subjected to virtual screening using molecular docking against VEGFR-2. Five lead compounds with improved binding affinities (-10.2 to -11.8&#xa0;kcal/mol) were synthesized and evaluated through MTT cytotoxicity assays, DPPH antioxidant assays, and VEGFR-2 kinase inhibition studies. The most promising candidate underwent comprehensive characterisation, including 100 ns molecular dynamics simulations, DFT calculations, kinase activity, and in silico toxicity predictions.</p> Results <p>BenTic(F) shows a paradigm shift of peptide-THIQ conjugate successfully, demonstrating a significant VEGFR-2 inhibitory potency (<i>IC₅₀</i> = 47.94 nM) with 2.6-fold improved activity compared to pazopanib (<i>IC₅₀</i> = 123.5 nM). The compound exhibited significant antioxidant activity (DPPH <i>IC₅₀</i> = 52.19 ± 0.36 µM) and optimal binding affinity (ΔG = -11.02&#xa0;kcal/mol; Ki = 18.09 µM) through five hydrophilic interactions with key VEGFR-2 residues (Asp241, Gly243) and hydrophobic interactions (Leu84, Leu214, Phe242). Strategic peptide conjugation enhanced aqueous solubility dramatically (HIA = 0.899 vs. HIA = 0.015 for Pazopanib) while maintaining drug-like properties (LogP = 2.7, TPSA = 139.6 Ų) within Lipinski parameters. Molecular dynamics simulations confirmed a stable allosteric site adjacent to hinge engagement and potential resistance circumvention through conserved residue anchoring. ADMET profiling revealed favourable safety characteristics with reduced hERG, DILI, and carcinogenicity risks, though ProTox-3 identified potential neurotoxicity requiring further evaluation.</p> Conclusions <p>BenTic(F) represents a promising peptide-THIQ conjugate that successfully integrates target-specific VEGFR-2 inhibition with antioxidant activity and enhanced pharmacokinetic properties. The computational predictions with experimental validation provide robust evidence for the potential of RCC. This work advances peptide-drug conjugate methodology while delivering a highly promising therapeutic candidate, warranting immediate in vivo evaluation and clinical translation, opening up a new path for a precision oncology approach for renal cell carcinoma (RCC) treatment.</p>

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Peptide-Tetrahydroisoquinoline (THIQ) Conjugated Derivatives as Dual-Targeting Therapeutics: Superior VEGFR-2 Inhibition and Antioxidant Activity against Renal Cell Carcinoma

  • 期刊论文

  • 发表日期：

    2025年10月10日

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  • Vidya Sagar Jerra,
  • Shaik Mohammed Sharif,
  • Rajamanikandan Sundararaj,
  • Srinivasadesikan Venkatesan

摘要

Background

Renal cell carcinoma (RCC) represents a therapeutic challenge due to aberrant angiogenesis and oxidative stress pathways, and more off-site target drugs. Current VEGFR-2 inhibitors like Tyrosine kinase inhibitors (TKIs) demonstrate limited efficacy and significant side effects, lacking selectivity, necessitating novel multi-targeted approaches. Peptide-drug conjugates offer promising avenues for enhanced specificity and reduced toxicity in cancer therapeutics. Over the past decades, computational design has given fast and more reliable results.

Objective

To design, synthesize, and evaluate novel peptide-(D)-tetrahydroisoquinoline (THIQ) conjugates targeting VEGFR-2 signalling and oxidative stress pathways in RCC through integrated computational tools and experimental approaches.

Methods

Five hundred peptide-THIQ conjugates were rationally designed and subjected to virtual screening using molecular docking against VEGFR-2. Five lead compounds with improved binding affinities (-10.2 to -11.8 kcal/mol) were synthesized and evaluated through MTT cytotoxicity assays, DPPH antioxidant assays, and VEGFR-2 kinase inhibition studies. The most promising candidate underwent comprehensive characterisation, including 100 ns molecular dynamics simulations, DFT calculations, kinase activity, and in silico toxicity predictions.

Results

BenTic(F) shows a paradigm shift of peptide-THIQ conjugate successfully, demonstrating a significant VEGFR-2 inhibitory potency (IC₅₀ = 47.94 nM) with 2.6-fold improved activity compared to pazopanib (IC₅₀ = 123.5 nM). The compound exhibited significant antioxidant activity (DPPH IC₅₀ = 52.19 ± 0.36 µM) and optimal binding affinity (ΔG = -11.02 kcal/mol; Ki = 18.09 µM) through five hydrophilic interactions with key VEGFR-2 residues (Asp241, Gly243) and hydrophobic interactions (Leu84, Leu214, Phe242). Strategic peptide conjugation enhanced aqueous solubility dramatically (HIA = 0.899 vs. HIA = 0.015 for Pazopanib) while maintaining drug-like properties (LogP = 2.7, TPSA = 139.6 Ų) within Lipinski parameters. Molecular dynamics simulations confirmed a stable allosteric site adjacent to hinge engagement and potential resistance circumvention through conserved residue anchoring. ADMET profiling revealed favourable safety characteristics with reduced hERG, DILI, and carcinogenicity risks, though ProTox-3 identified potential neurotoxicity requiring further evaluation.

Conclusions

BenTic(F) represents a promising peptide-THIQ conjugate that successfully integrates target-specific VEGFR-2 inhibition with antioxidant activity and enhanced pharmacokinetic properties. The computational predictions with experimental validation provide robust evidence for the potential of RCC. This work advances peptide-drug conjugate methodology while delivering a highly promising therapeutic candidate, warranting immediate in vivo evaluation and clinical translation, opening up a new path for a precision oncology approach for renal cell carcinoma (RCC) treatment.