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AI and pharmacophore-based screening, molecular docking, and dynamic simulation for identification of CDK6 inhibitors

Yana Xu1, Zhehan Wang2, Tianhua Yang3

  • 1Department of Pharmacy, Hangzhou Geriatric Hospital, Affiliated Hangzhou First People's Hospital Chengbei Campus, School of Medicine, Westlake University, Hangzhou, China.

European Journal of Medicinal Chemistry
|May 19, 2026
PubMed

Insights

Researchers identified potent inhibitors for the overactivated CDK6/Cyclin D3 complex, a target linked to poor prognosis in non-small cell lung cancer (NSCLC). Compound 2 shows significant promise for NSCLC treatment by inhibiting tumor cell proliferation.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Overactivation of the CDK6/Cyclin D3 complex is linked to poor prognosis in non-small cell lung cancer (NSCLC).
  • Targeting this complex with inhibitors offers potential new therapeutic strategies for NSCLC patients.

Purpose of the Study:

  • To rapidly identify novel inhibitors of the CDK6/Cyclin D3 complex using a multi-faceted virtual screening approach.
  • To evaluate the in vitro efficacy and mechanism of action of identified inhibitors against NSCLC.

Main Methods:

  • A mixed virtual screening workflow integrating artificial intelligence, pharmacophore modeling, and molecular docking was employed.
  • A library of 12,563 compounds was screened to identify potential CDK6/Cyclin D3 inhibitors.
  • In vitro assays were conducted to assess the inhibitory activity and anti-proliferative effects of lead compounds against NSCLC cell lines.

Main Results:

  • The screening workflow successfully identified multiple CDK6/Cyclin D3 inhibitors with a hit rate exceeding 40%.
  • Compound 2 demonstrated potent CDK6/Cyclin D3 inhibitory activity (IC50 = 38.6 nM) and significant proliferation-inhibitory effects against NSCLC cell lines (IC50 < 78 nM).
  • Kinetic simulations revealed that compound 2 binds to the ATP-binding pocket of CDK6, stabilizing its conformation via specific interactions.

Conclusions:

  • The study successfully identified potent CDK6/Cyclin D3 inhibitors, including compound 2, with promising anti-NSCLC activity.
  • Compound 2's potent inhibition and favorable binding interactions provide a strong foundation for developing novel NSCLC therapeutics.
  • The findings offer valuable insights into the structural basis for CDK6 inhibition, guiding future drug design efforts.
Keywords:
CDK6Cyclin D3Molecular dynamicsNSCLCPharmacophoreVirtual screening

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