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<p>Prostate cancer remains a significant oncological challenge, driven by molecular factors such as KLK3 (kallikrein-related peptidase 3). Text mining of 237,357 PubMed articles identified KLK3 as the most frequently cited protein (10,477 mentions in titles; 162,619 in abstracts), with strong co-mentions of AR, TMPRSS2, and ERG (<i>χ</i><sup>2</sup>, *<i>p</i>* &lt; 0.001). Structural modeling of KLK3 (PDB: 2ANY) using I-TASSER yielded a high-confidence 3D structure (C-score: 0.73), validated by Ramachandran analysis, with 99.5% of residues falling in favored regions. Phytochemical profiling of&#xa0;<i>Curcuma longa</i>&#xa0;revealed potent bioactive constituents, with leaf extracts showing the highest total phenolic (510.7 ± 0.07 µg/mL) and flavonoid (498.9 ± 0.05 µg/mL) content. LC–MS identified 23 bioactive compounds, which exhibited exceptional binding affinity. Virtual screening of FDA-approved drugs (−&#xa0;11.8 to −&#xa0;9.4 kcal/mol), food-derived compounds (−&#xa0;10.0 to −&#xa0;9.1 kcal/mol), and natural products (−&#xa0;11.4 to −&#xa0;8.8 kcal/mol) revealed significant differences in binding affinities. MK3207 showed the highest binding affinity (−&#xa0;11.7 kcal/mol), followed by MolPort-039-338-696 (−&#xa0;11.4 kcal/mol), with key interactions at PHE-110 and THR-167. In-silico docking shows that MK3207 exhibits the strongest binding affinity to KLK3 (− 11.7 kcal/mol), with accuracy validated by an RMSD of 0.195 Å. Pharmacokinetic and drug-likeness evaluation of MK3207 indicated moderate solubility (Log S: −&#xa0;4.58 to −&#xa0;5.02), high lipophilicity (consensus log <i>P</i><sub>o</sub>/<i>w</i>: 3.39), favorable drug-likeness (no PAINS/Lipinski violations, bioavailability score: 0.55, synthetic accessibility: 5.21). MD simulations (100 ns) confirmed stable KLK3–ligand binding (final RMSD: 4.3 Å protein, 3.1 Å ligand; average RMSD: 3.99 Å C-α, 3.97 Å backbone, 5.41 Å sidechain). The complex exhibited moderate flexibility (RMSF peaks: 1–4 Å), 28.32% secondary structure, and persistent interactions (hydrophobic: VAL-49, PHE-110; hydrogen bonds: THR-167, SER-213). MM-GBSA analysis revealed strong binding energy (−&#xa0;75.57 to −&#xa0;66.36 kcal/mol) and consistent ligand efficiency. This study bridges&#xa0;computational drug discovery&#xa0;and&#xa0;phytochemical analysis, nominating&#xa0;<i>Curcuma longa</i>&#xa0;derivatives and&#xa0;MK3207&#xa0;as promising KLK3 inhibitors for PC therapy.</p> Graphical abstract <p></p>

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Identifying drug targets and evaluating KLK3-targeted inhibitors for prostate cancer using in-silico and in-vitro approaches

  • 期刊论文

  • 发表日期：

    2025年9月11日

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  • Imran Zafar,
  • Shaista Shafiq,
  • Adil Jamal,
  • Mohamed Mohany,
  • Muhammad Shafiq,
  • Mohammad Amjad Kamal,
  • Najeeb Ullah Khan

摘要

Prostate cancer remains a significant oncological challenge, driven by molecular factors such as KLK3 (kallikrein-related peptidase 3). Text mining of 237,357 PubMed articles identified KLK3 as the most frequently cited protein (10,477 mentions in titles; 162,619 in abstracts), with strong co-mentions of AR, TMPRSS2, and ERG (χ2, *p* < 0.001). Structural modeling of KLK3 (PDB: 2ANY) using I-TASSER yielded a high-confidence 3D structure (C-score: 0.73), validated by Ramachandran analysis, with 99.5% of residues falling in favored regions. Phytochemical profiling of Curcuma longa revealed potent bioactive constituents, with leaf extracts showing the highest total phenolic (510.7 ± 0.07 µg/mL) and flavonoid (498.9 ± 0.05 µg/mL) content. LC–MS identified 23 bioactive compounds, which exhibited exceptional binding affinity. Virtual screening of FDA-approved drugs (− 11.8 to − 9.4 kcal/mol), food-derived compounds (− 10.0 to − 9.1 kcal/mol), and natural products (− 11.4 to − 8.8 kcal/mol) revealed significant differences in binding affinities. MK3207 showed the highest binding affinity (− 11.7 kcal/mol), followed by MolPort-039-338-696 (− 11.4 kcal/mol), with key interactions at PHE-110 and THR-167. In-silico docking shows that MK3207 exhibits the strongest binding affinity to KLK3 (− 11.7 kcal/mol), with accuracy validated by an RMSD of 0.195 Å. Pharmacokinetic and drug-likeness evaluation of MK3207 indicated moderate solubility (Log S: − 4.58 to − 5.02), high lipophilicity (consensus log Po/w: 3.39), favorable drug-likeness (no PAINS/Lipinski violations, bioavailability score: 0.55, synthetic accessibility: 5.21). MD simulations (100 ns) confirmed stable KLK3–ligand binding (final RMSD: 4.3 Å protein, 3.1 Å ligand; average RMSD: 3.99 Å C-α, 3.97 Å backbone, 5.41 Å sidechain). The complex exhibited moderate flexibility (RMSF peaks: 1–4 Å), 28.32% secondary structure, and persistent interactions (hydrophobic: VAL-49, PHE-110; hydrogen bonds: THR-167, SER-213). MM-GBSA analysis revealed strong binding energy (− 75.57 to − 66.36 kcal/mol) and consistent ligand efficiency. This study bridges computational drug discovery and phytochemical analysis, nominating Curcuma longa derivatives and MK3207 as promising KLK3 inhibitors for PC therapy.

Graphical abstract