Identification of CXCR4 inhibitors as a key therapeutic small molecule in renal fibrosis.

The final stage of almost all chronic kidney diseases is renal fibrosis. Simple wounds or persistent inflammation can cause tissue inflammation, which, in the case of the kidney, results in scarring. Vascular sclerosis, tubulointerstitial fibrosis and glomerular fibrosis are all types of kidney fibrosis. Renal damage and fibrosis are caused by elevated expression of CXCR4. This study aimed to identify possible pharmacological agents which could bind to and inhibit isoform I of CXCR4 and determine their strength of interactions. The I-TASSER, Galaxyweb and Robetta were used to predict and refine the structure of the CXCR4 protein. ModBase was used to improve the loops, and then the quality was evaluated by using the ERRAT value (92.15) and Ramachandran plot. The improved 3D structure was subjected to small molecule database docking using Maestro (from Schrodinger) and the glide module. GROMACS was used to simulate molecules with the three top low glide scores and the best ADME properties. The best glide score was achieved by ligand ID 4990 (-11.5). Simulations, free energy landscape and residue decomposition analysis revealed that 4990 interacted more consistently with CXCR4 than the other two small molecules.Communicated by Ramaswamy H. Sarma.

Identification of neo-andrographolide compound targeting NS1 Lys14: an important residue in NS1 activity driving dengue pathogenesis.

Dengue virus is part of the flaviviruses that spread through the Aedes mosquito species and causes vascular leakage and multiple organ failure. The non-structural protein 1 (NS1) is involved in the replication of Dengue virus. The glycosylated dimeric and hexameric form of NS1 is the biologically active form. Therefore, in this study, the NS1 protein was modeled in dimeric form which is predominantly present inside the host cell. The dimeric model was validated and it was glycosylated at ASN130 and ASN207 with oligomannose. This model was simulated for 100 ns to retrieve the global minima structure. The andrographolide and its four derivatives were docked non-specifically against the dimeric glycosylated NS1 protein. The neo-andrographolide compound showed strong interactions with favorable binding energy of -8.2 kcal/mol and electrostatic binding affinity of -8.9 kcal/mol. All docked ligand-protein complexes were simulated for 100 ns. The molecular dynamics simulation analysis comprising of root mean square deviation and fluctuation, the radius of gyration, hydrogen bonding, potential energy, principal component analysis, SASA, DSSP, Free energy Landscape, MM-PBSA and Electrostatic binding affinity revealed about the stability of complex systems. These andrographolide and its derivatives was found to be interacting with Lys14 and this residue was reported as one of the important residues in NS1 activity. Among all compounds, the neo-andrographolide compound has the promising potential to inhibit the activity of the NS1 which is necessary for the Dengue virus replication.Communicated by Ramaswamy H. Sarma.

The dimeric NS1 protein structure was modeled and glycosylated at ASN130 and ASN 207 with Oligo-mannose.The minimized structure was used for molecular docking studies with andrographolide and its derivatives.The Lys14 residue is well interfered by all compounds but based on molecular dynamics and binding affinity studies, neo-andrographolide compound has the promising potential to inhibit the activity of the NS1.

Identifying novel small molecule antagonists for mLST8 protein using computational approaches.

Mammalian lethal with SEC13 protein 8 (mLST8), is an indispensable protein subunit of mammalian target of rapamycin (mTOR) signaling pathway that interacts with the kinase domain of mTOR protein, thereby stabilizing its active site. Experimental studies reported the over expression of mLST8 in human colon and prostate cancers by activation of both mTORC1/2 complexes and subsequent downstream substrates leading to tumor progression. Considering its role, targeting mLST8 protein would be a therapeutic approach against tumor progression in colon and prostate cancers. Hence, using in silico structure based drug design approach, the comparative binding patterns of 1,1'-binapthyl-2,2'diol (BINOL), 1-(2-carboxynaphth-1yl)-2-naphthoic acid (SCF-12) and their analogs in the cavity of mLST8 were explored. ADME and binding energy calculations led to the identification of five compounds with favorable Glide (G) scores and implicated the importance of Asn132 and Gln225 as key binding residues. Molecular dynamics (MD) simulations and free energy landscape (FEL) approaches helped in elucidating the binding mechanism and suggested the possibility of ligands 1-3 namely, ZINC01765622, ZINC62723702 and ZINC02576980 to be promising antagonists for mLST8. Thus, this study substantiates the prospect of targeting mLST8 protein using potent hits which could hinder tumor progression in colon and prostate cancers.

Molecular docking and dynamics studies of 4-anilino quinazolines for epidermal growth factor receptor tyrosine kinase to find potent inhibitor.

A series of novel 4-anilino quinazoline derivatives were taken based on the literature study and optimized with Autodock version 4.2 and molecular dynamics (MD) protocol to investigate the interaction between the target compounds and the amino acid residues of target protein epidermal growth factor receptor (EGFR) tyrosine kinase (PDB ID: 1M17). The free energies of binding and inhibition constants (Ki) of the docked ligands were calculated by the Lamarckian genetic algorithm (LGA). The docking results showed that the compounds SGQ4, DMUQ5, 6AUQ6, and PTQ8 had produced significant docking affinity for the protein tyrosine kinase with the binding energy of -7.46, -7.31, -6.85, and -6.74 kcal/mol, respectively, compared to the standard inhibitor Erlotinib (binding energy: -3.84 kcal/mol). Furthermore, molecular dynamics simulations (MDS) were performed using Gromacs to investigate the stability of a ligand-protein complex. The combined analysis of root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of 1M17 protein with docked ligands reveals that 1M17 protein has more stability when it interacts reacts with the inhibitor. Molecular descriptive properties and toxicity profile predicted by software. All the designed molecules passed Lipinski's rule of five successfully and they were found to be safe.