ABSTRACT
The Human Chemokine (C-C motif) ligand 19 (CCL19) protein plays a major role in rheumatic and autoimmune diseases. The 3D models of the CCL19 and its receptor CCR7 are generated using homology modeling and are validated using standard computational protocols. Disulfide bridges identified in 3D model of CCL19 protein give extra stability to the overall protein structure. The active site region of protein CCL19, containing N-terminal amino acid residues (Gly22 to Leu31), is predicted using in silico techniques. Protein-protein docking studies are carried out between the CCL19 and CCR7 proteins to analyse the active site binding interactions of CCL19. The binding domain of CCL19 is subjected to structure-based virtual screening of small molecule databases, and identified several bioisosteric ligand molecules having pyrrolidone and piperidone pharmacophores. The prioritized ligands with acceptable ADME properties are reported as new leads for the design of potential CCL19 antagonists for rheumatic and autoimmune disease therapies.
Subject(s)
Autoimmune Diseases/drug therapy , Chemokine CCL19/chemistry , Chemokine CCL19/metabolism , Computer Simulation , Receptors, CCR7/chemistry , Receptors, CCR7/metabolism , Rheumatic Diseases/drug therapy , Amino Acid Sequence , Catalytic Domain , Conserved Sequence , Disulfides/metabolism , Drug Evaluation, Preclinical , Humans , Ligands , Molecular Docking Simulation , Protein Binding , Protein Domains , Protein Structure, Secondary , Solvents , Structural Homology, ProteinABSTRACT
Cancer is a class of diseases characterized by uncontrolled cell growth. Every year more than 2 million people are affected by the disease. Rho family proteins are actively involved in cytoskeleton regulation. Over-expression of Rho family proteins show oncogenic activity and promote cancer progression. In the present work RhoG protein is considered as novel target of cancer. It is a member of Rho family and Rac subfamily protein, which plays pivotal role in regulation of microtubule formation, cell migration and contributes in cancer progression. In order to understand the binding interaction between RhoG protein and the DH domain of Ephexin-4 protein, the 3D structure of RhoG was evaluated and Molecular Dynamic Simulations was performed to stabilize the structure. The 3D structure of RhoG protein was validated and active site identified using standard computational protocols. Protein-protein docking of RhoG with Ephexin-4 was done to understand binding interactions and the active site structure. Virtual screening was carried out with ligand databases against the active site of RhoG protein. The efficiency of virtual screening is analysed with enrichment factor and area under curve values. The binding free energy of docked complexes was calculated using prime MM-GBSA module. The SASA, FOSA, FISA, PISA and PSA values of ligands were carried out. New ligands with high docking score, glide energy and acceptable ADME properties were prioritized as potential inhibitors of RhoG protein.
Subject(s)
Antineoplastic Agents/chemistry , Drug Design , Molecular Docking Simulation , Molecular Dynamics Simulation , rho GTP-Binding Proteins/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Drug Discovery , Ligands , Molecular Conformation , Protein Binding , ROC Curve , Solvents , Structure-Activity Relationship , rho GTP-Binding Proteins/antagonists & inhibitorsABSTRACT
The development of novel antituberculosis therapeutic molecules is a global health concern. Complex gene expression in Mycobacterium tuberculosis is mediated mainly by various sigma factors. The SigK protein binds to RNA polymerase, facilitating the expression of genes encoding the antigenic proteins mpt70 and mpt83. The anti-SigK protein is a negative regulator of SigK and inhibits the initiation of transcription. This study focuses on the interactions between SigK and the N-terminal domain of anti-SigK. The 3D structures of SigK (187 residues) and the N-terminal domain of anti-SigK (92 residues) are elucidated, using the crystal structures of the A and B chains of sigma E and anti-sigma ChrR of Rhodobacter spheroides (PDB code: 2Q1Z) as templates, respectively. Molecular dynamic simulations were performed for the SigK and anti-SigK proteins to refine their structures. The predicted active sites of SigK and anti-SigK and the results of protein-protein docking studies revealed the residues that are important for binding. The models generated and the binding site residues identified in this work throw new light on the interactions between the sigma K and anti-sigma K proteins, which should further aid the modulation of antigenic protein production in Mycobacterium tuberculosis.
