DOI: 10.6084/m9.figshare.12000012
title: Potential target identification for breast cancer and screening of small molecule inhibitors: A bioinformatics approach

description: In the current study, we investigated the role of PAK1 (P21 (RAC1) Activated Kinase 1) gene in breast cancer and to this end, we performed differential gene expression analysis of PAK1 in breast cancer tissues compared to the normal adjacent tissue. We also studied its significance in protein-protein interaction (PPI) network, and analysed biological pathways, cellular processes, and role of PAK1 in different diseases. We found PAK1 to have significant role in breast cancer pathways such as integrin signaling, axonal guidance signaling, signaling by Rho family GTPases, ERK5 signaling. Additionally, it has been found as hub gene in PPI network, suggesting its possible regulatory role in breast carcinogenesis. Moreover, PAK1 had role in progression of various diseases as neoplasia, tumorigenesis, lymphatic neoplasia. Thereby, PAK1 can be used as a therapeutic target in breast cancer. Further, we put our efforts in identification of potential small molecules inhibitors against PAK1 by developing a composite virtual screening protocol involving molecular dynamics (MD) and molecular docking. The chemical library of compounds from NCI diversity sets, Pubchem and eMolecules were screened against PAK1 protein and hits which showed good binding affinity were considered for MD simulation study. Moreover, to assess binding of selected hits, MMGBSA (Molecular Mechanics-Generalized Born Surface Area) analysis was performed using AMBER (Assisted Model Building with Energy Refinement) package. MMGBSA calculations exhibited that the identified ligands showed good binding affinity with PAK1. HighlightsThe PAK1 has been found to be upregulated in breast cancer samples and is a potential oncogene playing role in different cellular functions and processes.The molecular docking studies revealed ligands showed good binding affinity towards PAK1 protein.The residues Glu345, Leu347, Thr406, Asp299, Asp393 and Gly350 were found to make H-bond interactions with small molecule inhibitors.The residues Ile276, Val284, Ala297, Tyr346, Leu396 and Asp407 were found to make hydrophobic interactions.The RMSD analysis confirmed stability of complexes throughout 40 ns production period.The MD simulations studies revealed the binding site flexibility, binding free energy of complexes and per-residue contribution in ligand binding. The PAK1 has been found to be upregulated in breast cancer samples and is a potential oncogene playing role in different cellular functions and processes. The molecular docking studies revealed ligands showed good binding affinity towards PAK1 protein. The residues Glu345, Leu347, Thr406, Asp299, Asp393 and Gly350 were found to make H-bond interactions with small molecule inhibitors. The residues Ile276, Val284, Ala297, Tyr346, Leu396 and Asp407 were found to make hydrophobic interactions. The RMSD analysis confirmed stability of complexes throughout 40 ns production period. The MD simulations studies revealed the binding site flexibility, binding free energy of complexes and per-residue contribution in ligand binding. Communicated by Ramaswamy H. Sarma