Computational design of new protein kinase D 1 (PKD1) inhibitors: homology-based active site prediction, energy-optimized pharmacophore, docking and database screening.

Protein kinase D 1 (PKD1) overexpression has a well-validated role in cancer progression and its inhibitors have defined a protective role-play of PKD1 for various cancers such as prostate, pancreatic and noninvasive breast cancers, and more. Therefore, the current research was aimed at designing new PKD1 inhibitors combining different ligand- and structure-based computational drug designing methodologies. Initially, the three-dimensional structure of PKD1's active site was computationally modeled, corrected using molecular dynamic simulations and validated for docking experiments. The highest active PKD1 inhibitor was used to develop a structure-based energetic pharmacophore (e-pharmacophore) model, and a final model was selected with five structural features (Pmodel_AADHR). Pmodel_AADHR was validated and used for database screening to obtain new hits against PKD1. These newly retrieved hits were docked against our PKD1 protein model, and those displaying essential interactions are reported herein as new hits, which could serve as new leads for cancer research, especially pancreatic cancer.