Interactions of selected indole derivatives with COX-2 and their in silico structure modifications towards the development of novel NSAIDs

Cyclooxygenase-2 (COX-2) is an important enzyme responsible for the formation of potent inflammatory mediators like prostaglandins, prostacyclin and thromboxane. Hence, inhibition of COX-2 is one of the best ways to control the inflammation. Non-steroidal anti-inflammatory drugs can control inflammation by inhibiting Cyclooxygenase. Selective inhibition of COX-2 is preferable over the inhibition of COX-1 because of the fewer adverse effects produced. Molecular modeling and docking of 134 selected indole compounds were done against COX-2. The pharmacophore-based in silico structural modifications of the best scored compounds were carried out in order to enhance the binding affinity and selectivity. The modification resulted in derivatives with better binding energies than that of known COX-2 inhibitors. The four best derivatives in terms of the binding energies were selected and their binding stabilities were studied by molecular dynamics simulation methods.     

Relibase: design and development of a database for comprehensive analysis of protein-ligand interactions

Knowledge discovery from the exponentially growing body of structurally characterised protein-ligand complexes as a source of information in structure-based drug design is a major challenge in contemporary drug research. Given the need for powerful data retrieval, integration and analysis tools, Relibase was developed as a database system particularly designed to handle protein-ligand related problems and tasks. Here, we describe the design and functionality of the Relibase core database system. Features of Relibase include, e.g. the detailed analysis of superimposed ligand binding sites, ligand similarity and substructure searches, and 3D searches for protein-ligand and protein-protein interaction patterns. The broad range of functions provided in Relibase and its high level of data integration, along with its flexible and intuitive interface, makes Relibase an invaluable data mining tool which can significantly enhance the drug development process. An example, illustrating a 3D query for quarternary ligand nitrogen atoms interacting with aromatic ring systems in proteins, a pattern found in pharmaceutically relevant target proteins such as, e.g. acetylcholine-esterase, is discussed.     

Utilising structural knowledge in drug design strategies: applications using Relibase

The concept of structure-based drug design is based upon an in-depth understanding of the principles of molecular recognition. Despite our lack of a thorough comprehension of these principles, the wealth of protein structures available opens up unprecedented possibilities for new insights from the analysis of these data. Unravelling universal rules of molecular recognition is certainly one of the most appealing goals. But our knowledge is enhanced also when studying the specific determinants that characterise single targets or target families only, and the factors governing and discriminating their recognition properties.Here, we illustrate how the structure-based design process can benefit from the consequent incorporation of database query tools. We discuss representative examples to address issues such as protein flexibility, water molecules in binding pockets, and ligand specificity as some of the most critical aspects of drug design. All studies are carried out using our database system Relibase. We also show the application of Relibase in searching for preferred geometrical patterns between interacting molecular fragments.     

Exploring the energy landscapes of molecular recognition by a genetic algorithm: Analysis of the requirements for robust docking of HIV-1 protease and FKBP-12 complexes

Energy landscapes of molecular recognition are explored by performing “semi-rigid” docking of FK-506 and rapamycin with the Fukisawa binding protein (FKBP-12), and flexible docking simulations of the Ro-31-8959 and AG-1284 inhibitors with HIV-1 protease by a genetic algorithm. The requirements of a molecular recognition model to meet thermodynamic and kinetic criteria of ligand-protein docking simultaneously are investigated using a family of simple molecular recognition energy functions. The critical factor that determines the success rate in predicting the structure of ligand-protein complexes is found to be the roughness of the binding energy landscape, in accordance with a minimal frustration principle. The results suggest that further progress in structure prediction of ligand-protein complexes can be achieved by designing molecular recognition energy functions that generate binding landscapes with reduced frustration. © 1996 Wiley-Liss, Inc.     

Predicting molecular interactions and inducible complementarity: Fragment docking of fab-peptide complexes

Antibody-antigen interactions are representative of a broad class of receptor-ligand interactions involving both specificity and potential inducible complementarity. To test possible mechanisms of antigenantibody recognition and specificity computationally, we have used a Metropolis Monte Carlo algorithm to dock fragments of the epitope Glu-Val-Val-Pro-His-Lys-Lys to the X-ray structures of both the free and the complexed Fab of the antibody B13I2 (raised against the C-helix of myohemerythri). The fragments Pro-His and Val-Pro-His, which contain residues experimentally identified as important for binding, docked correctly to both structures, but all tetrapeptide and larger fragments docked correctly only to the complexed Fab, even when torsional flexibility was added to the ligand. However, only tetrapeptide and larger fragments showed significantly more favorable energies when docked to the complexed Fab coordinates than when docked to either the free Fab or a non-specific site remote from the combining site. Comparison of the free and complexed B13I2 structures revealed that atoms within 5 Å of Val-Pro-His showed little movement upon peptide binding, but atoms within 5 Å of the other four epitope residues showed greater movements. These results computationally distinguish recognition and binding processes with practical implications for drug design strategies. Overall, this new fragment docking approach establishes distinct roles for the “lock-and-key” (recognition) and the “handshake” (binding) paradigms in antibody-antigen interaction, suggests an incremental approach to incorporating flexibility in computational docking, and identifies critical regions within receptor binding sites for ligand recognition. © 1994 Wiley-Liss, Inc.     

Discovery of promising FtsZ inhibitors by E-pharmacophore, 3D-QSAR,molecular docking study,and molecular dynamics simulation

Filamentous temperature-sensitive protein Z (FtsZ), playing a key role in bacterial cell division, is regarded as a promising target for the design of antimicrobial agent. This study is looking for potential high-efficiency FtsZ inhibitors. Ligand-based pharmacophore and E-pharmacophore, virtual screening and molecular docking were used to detect promising FtsZ inhibitors, and molecular dynamics simulation was used to study the stability of protein-ligand complexes in this paper. Sixty-three inhibitors from published literatures with pIC₅₀ ranging from 2.483 to 5.678 were collected to develop ligand-based pharmacophore model. 4DXD bound with 9PC was selected to develop the E-pharmacophore model. The pharmacophore models validated by test set method and decoy set were employed for virtual screening to exclude inactive compounds against ZINC database. After molecular docking, ADME analysis, IFD docking and MM-GBSA, 8 hits were identified as potent FtsZ inhibitors. A 50?ns molecular dynamics simulation was implemented on the compounds to assess the stability between potent inhibitors and FtsZ. The results indicated that the candidate compounds had a high docking score and were strongly combined with FtsZ by forming hydrogen bonding interactions with key amino acid residues, and van der Waals forces and hydrophobic interactions had significant contribution to the stability of the binding. Molecular dynamics simulation results showed that the protein-ligand compounds performed well in both the stability and flexibility of the simulation process.     

Understanding the binding of quinoline amines with human serum albumin by spectroscopic and induced fit docking methods

Seven new quinoline-based bioorganic compounds were prepared by solvent-free synthesis and characterized using spectral techniques. The binding of these compounds with human serum albumin (HSA) was investigated by multi-spectroscopic methods. The quenching of Trp fluorescence upon addition of these compounds to HSA confirmed their significant binding. The quenching analysis at three different temperatures revealed that the complex formation is static and the reaction is entropy driven, spontaneous, and exothermic. Hydrogen bonds and van der Waals forces mainly contributed in the interactions as confirmed by the negative ΔH and ΔS values as well as molecular docking. The results from the circular dichroism (CD) spectroscopy indicated the minimal conformational changes of the protein upon binding with these quinoline compounds. The specific binding site and mode of interactions with HSA were also modeled using induced fit molecular docking procedure and their binding site was found to be in the interface of domains II and III, which is similar to the binding of the drug iodipamide with serum albumin.

Communicated by Ramaswamy H. Sarma     

Binding mode of Pyridoclax to myeloid cell leukemia-1 (Mcl-1) revealed by nuclear magnetic resonance spectroscopy,docking and molecular dynamics approaches

Abstract

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family proteins. Its amplification is one of the most frequent genetic aberrations found in human cancers. Pyridoclax, a promising BH3 mimetic inhibitor, interacts directly with Mcl-1 and induces massive apoptosis at a concentration of 15?µM in combination with anti-Bcl-x_L strategies in chemo-resistant ovarian cancer cell lines. In this study, a combined experimental and theoretical approach was used to investigate the binding mode of Pyridoclax to Mcl-1. The representative poses generated from dynamics simulations compared with NMR data revealed: (i) Pyridoclax bound to P1 and P2 pockets of Mcl-1 BH3 binding groove through its styryl and methyl groups establishing mainly hydrophobic contacts, (ii) one of the ending pyridines interacts through electrostatic interaction with K234 side chain, a negatively charged residue present only in this position in Mcl-1.

Communicated by Ramaswamy H. Sarma