Exploring a model of a chemokine receptor/ligand complex in an explicit membrane environment by molecular dynamics simulation: the human CCR1 receptor

The seven transmembrane helices G-protein-coupled receptors (GPCRs) form one of the largest superfamilies of signaling proteins found in humans. Homology modeling, molecular docking, and molecular dynamics (MD) simulation were carried out to construct a reliable model for CCR1 as one of the GPCRs and to explore the structural features and the binding mechanism of BX471 as one of the most potent CCR1 inhibitors. In this study, BX471 has been docked into the active site of the CCR1 protein. After docking, one 20 ns MD simulation was performed on the CCR1-ligand complex to explore effects of the presence of lipid membrane in the vicinity of the CCR1-ligand complex. At the end of the MD simulation, a change in the position and orientation of the ligand in the binding site was observed. This important observation indicated that the application of MD simulation after docking of ligands is useful. Explorative runs of molecular dynamics simulation on the receptor-ligand complex revealed that except for Phe85, Phe112, Tyr113, and Ile259, the rest of the residues in the active site determined by docking are changed. The results obtained are in good agreement with most of the experimental data reported by others. Our results show that molecular modeling and rational drug design for chemokine targets is a possible approach.     

Structure–activity relationship of polyamine conjugates for uptake via polyamine transport system

Structural Chemistry - High toxicity of anticancer drugs led to development of targeted drug delivery directly to the specific organs. Polyamine transport system (PTS) of mammalian cells is one of...     

Theoretical studies of 1,4-dihydropyridine-3,5-dicarboxamides as possible inhibitors of Mycobacterium tuberculosis enoyl reductase

Abstract  

The binding affinity of some novel 1,4-dihydropyridine-3,5-dicarboxamides to enoyl-ACP reductase (InhA) from M. tuberculosis was studied by the docking method. A molecular dynamics simulation lasting 230 ns in total was performed for 19 ligand–enzyme complexes to calculate the binding free energies of these ligands to the enzyme. All of the studied compounds stayed in the active site. An energetics analysis revealed that the van der Waals share is more important than electrostatic in binding of all ligands to the active site.     

Anti-cancer,anti-oxidant and molecular docking studies of thiosemicarbazone indole-based derivatives

Based on the structural elements of bioactive 3-substituted indoles, a new series of indole–thiosemicarbazone hybrid derivatives were designed, synthesized, and well-characterized using different spectral techniques. The intended scaffolds were screened for their in vitro anti-proliferative activities against breast cancer (MCF-7), lung cancer (A-549), and liver cancer (Hep-G2) cell lines, as well as their anti-oxidant properties. Cytotoxicity studies revealed that compound 6n was the most potent, at least threefold more potent than the commercially available reference drug etoposide, against A-549. In addition, morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis confirmed induction of apoptosis in the A-549 cells by compound 6n. In order to validate the experimental results, molecular studies were performed to achieve the possible binding interactions of the most potent compound (6n) and colchicine with tubulin as well as ANP with ATPase domain of topoisomerase IIα active sites. Moreover, the radical scavenging potential of the final derivatives was found to be excellent with the range of 0.015–0.630 µM, comparable to the standard ascorbic acid (0.655 µM).