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The over-expression of Polo-like kinase-1 (PLK1) is associated with cancer prognosis due to its pivotal role in cell proliferation. The N-terminal catalytic domain (NCD) and C-terminal polo box domain (PBD) of PLK1 are critical for the activity of the protein. Drugs that inhibit PLK1 by targeting these domains are on clinical trials, but so far, none has been approved by FDA. Thus, this study targets the two domains of PLK1 to identify compounds with inhibitory potential. Four validated e-pharmacophore models from NCD (PDB ID: 2OU7 and 4J52) and PBD (PDB ID: 5NEI and 5NN2) were used to screen over 26,000 natural compounds from NPASS database. Hits were identified after the well-fitted compounds were subjected to molecular docking study and ADME prediction. The pIC50 and electronic behaviour of the identified hits selectively targeting NCD and PBD of PLK1 were predicted via an externally validated QSAR model and quantum mechanics. The results showed that CAA180504, CAA197326, CAA74619, CAA328856 modulating PLK1 at NCD, and CBB130581, CBB230713, CBB206123, CBB12656 and CBB267117 modulating PLK1 at PBD had better molecular docking scores, pharmacokinetics and drug-like properties than NCD (volasertib) and PBD (purpurogallin) reference inhibitors. The compounds all had satisfactory inhibitory (pIC50) values which range from 6.187 to 7.157. The electronic behaviours of understudied compounds using HOMO/LUMO and global descriptive parameters revealed the atomic portion of the compounds prone to donating and accepting electrons. In conclusion, the hit compounds identified from the library of natural compounds are worthy of further experimental validation. Communicated by Ramaswamy H. Sarma

Virtual screening of natural compounds as selective inhibitors of polo-like kinase-1 at C-terminal polo box and N-terminal catalytic domain