Background: P-21 activating kinase 4 (PAK4) is implicated in poor prognosis of many cancers, especially in the
progression of Triple Negative Breast Cancer (TNBC). The present study was aimed at designing some potential drug
candidates as PAK4 inhibitors for breast cancer therapy.
Objective: This study aimed to finding novel inhibitors of PAK4 from natural compounds using computational approach.
Methods: An e-pharmacophore model was developed from docked PAK4-coligand complex and used to screen over a
thousand natural compounds downloaded from BIOFACQUIM and NPASS databases to match a minimum of 5 sites for
selected (ADDDHRR) hypothesis. The robustness of the virtual screening method was accessed by well-established
methods including EF, ROC, BEDROC, AUAC, and the RIE. Compounds with fitness score greater than one were filtered
by applying molecular docking (HTVS, SP, XP and Induced fit docking) and ADME prediction. Using Machine learningbased approach QSAR model was generated using Automated QSAR. The computed top model kpls_des_17 (R2= 0.8028,
RMSE = 0.4884 and Q2 = 0.7661) was used to predict the pIC50 of the lead compounds. Internal and external validations
were accessed to determine the predictive quality of the model. Finally the binding free energy calculation was computed.
Results: The robustness/predictive quality of the models were affirmed. The hits had better binding affinity than the
reference drug and interacted with key amino acids for PAK4 inhibition. Overall, the present analysis yielded three potential
inhibitors that are predicted to bind with PAK4 better than reference drug tamoxifen. The three potent novel inhibitors
vitexin, emodin and ziganein recorded IFD score of -621.97 kcal/mol, -616.31 kcal/mol and -614.95 kcal/mol, respectively
while showing moderation for ADME properties and inhibition constant.
Conclusion: It is expected that the findings reported in this study may provide insight for designing effective and less toxic
PAK4 inhibitors for triple negative breast cancer.