Protein Alpha Shape (PAS) Dock: A new gaussian-based score function suitable for docking in homology modelled protein structures

Abstract

Protein Alpha Shape (PAS) Dock is a new empirical score function suitable for virtual library screening using homology modelled protein structures. Here, the score function is used in combination with the geometry search method Tabu search. A description of the protein binding site is generated using gaussian property fields like in Protein Alpha Shape Similarity Analysis (PASSA). Gaussian property fields are also used to describe the ligand properties. The overlap between the receptor and ligand hydrophilicity and lipophilicity fields is maximised, while minimising steric clashes. Gaussian functions introduce a smoothing of the property fields. This makes the score function robust against small structural variations, and therefore suitable for use with homology models. This also makes it less critical to include protein flexibility in the docking calculations. We use a fast and simplified version of the score function in the geometry search, while a more detailed version is used for the final prediction of the binding free energies. This use of a two-level scoring makes PAS-Dock computationally efficient, and well suited for virtual screening. The PAS-Dock score function is trained on 218 X-ray structures of protein- ligand complexes with experimental binding affinities. The performance of PAS-Dock is compared to two other docking methods, AutoDock and MOE-Dock, with respect to both accuracy and computational efficiency. According to this study, PAS-Dock is more computationally efficient than both AutoDock and MOE-Dock, and gives a better prediction of the free energies of binding. PAS-Dock is also more robust against structural variations than AutoDock.

Is that Possible to Design the Versatile Inhibitors for H1N1, H5N1, H5N2, and H5N7?

“…The ligand-based pharmacophore map was created from Lu's study [9]. Additionally, the map was consisted with Shie's study [20]. Accordingly, the result was reliable.…”

“…Docking score (D.S.) was employed to score the docking results [19], [20] III. RESULT AND DISCUSSION…”

Improving molecular docking through eHiTS’ tunable scoring function

“…The scoring function is trained to reproduce crystallographic or NMR binding modes. Common examples of knowledge based scoring functions include PMF [13], DrugScore [14] and PAS-Dock [15].…”

Design of Selective Inhibitors of Tyrosine Kinase 2

“…In a recent publication, we predicted the 3D structures of the tyrosine kinase domains of Jak2 and Tyk2 by homology modelling, and suggested functional groups for a selective inhibitor of Tyk2 based on Protein Alpha Shape Similarity Analysis (PASSA) [20]. PASSA is a new method for mapping protein binding sites, and is especially suited for protein structures predicted by homology modelling.…”

“…Activated Janus kinases autophosphorylate [3] and phosphorylate the cytokine receptors with which they are associated, providing binding sites for the Signal Transducers and Activators of Transcription (STAT) family of transcription factors [8]. The Jaks catalyse phosphorylation of the STAT proteins (seven isoforms, STAT1-4, STAT5A-B and STAT6) [12], which occurs by This work utilised previously suggested functional groups for a selective Tyk2 inhibitor [20] in a pharmacophore search of the database of the National Cancer Institute (NCI). The resulting structures were tested for binding to Tyk2 by computational docking in a homology model of Tyk2.…”