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Putative Anti-Cancer Drug Candidate Targeting the 'PLK-1-Polo-Box Domain' by High Throughput Virtual Screening: A

Shazi Shakil1, Mohammed F Abuzinadah2

  • 1King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

Critical Reviews in Eukaryotic Gene Expression
|November 4, 2019
PubMed

Insights

Researchers discovered a novel cancer drug candidate targeting Polo-like-kinase-1 (PLK-1) Polo-Box-Domain (PBD). This new inhibitor, SHAZ-i, shows potent activity by binding to the PLK-1

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Structural Biology

Background:

  • Polo-like-kinase-1 (PLK-1) is a key regulator of cell division and a validated cancer target.
  • Existing PLK-1 Polo-Box-Domain (PBD) inhibitors traditionally target a small 'cleft', overlooking a larger, more complex binding site.
  • Novel therapeutic strategies are needed to effectively inhibit PLK-1 activity in cancer treatment.

Purpose of the Study:

  • To discover novel inhibitors targeting the trimodular 'Y'-pocket of the PLK-1 PBD.
  • To identify potent and drug-like small molecules with improved binding affinity and specificity.
  • To explore new therapeutic avenues for cancer by targeting PLK-1.

Main Methods:

  • High-throughput structure-based virtual screening (SBVS) of over 5 million compounds against the PLK-1 'Y'-pocket.
  • Multi-stage filtering including VINA score, toxicity, drug-likeness, and medicinal chemistry assessments.
  • Detailed analysis of ligand-protein interactions and binding free energy (ΔG).

Main Results:

  • A single top ligand, designated 'SHAZ-i' (3-{2-[(2-Methyl-2-propanyl)sulfonyl]phenyl}-5-phenyl-1,2-oxazole-4-carboxamide), was identified.
  • SHAZ-i demonstrated robust interactions with 15 amino acid residues within the target 'Y'-pocket, achieving a ΔG of -7.8 kcal/mol.
  • The identified compound exhibited a favorable pharmacokinetic profile with no predicted adverse effects.

Conclusions:

  • SHAZ-i represents a potent inhibitor candidate for the PLK-1 PBD, specifically targeting the trimodular 'Y'-pocket.
  • This molecule could serve as a foundational 'seed' for the development of next-generation PLK-1 inhibitors.
  • The findings offer a promising new direction for developing targeted cancer therapies.

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