Identification of oxazolo[4,5-g]quinazolin-2(1H)-one Derivatives as EGFR Inhibitors for Cancer Prevention.

OBJECTIVE: Abnormal expression of EGFR (epidermal growth factor receptor) results in different types of human tumors. Quinazoline-containing derivative signify an attractive platform for EGFR inhibitors. The present study aims to discover the potential binders of a group of compounds belonging to oxazolo[4,5-g]quinazoline-2(1H)-one derivative as EGFR inhibitors. METHODS: We apply multiple computational procedures, including pharmacophore-based virtual screening methods, to perform a preliminary screening against EGFR over compounds belonging to oxazolo[4,5-g]quinazoline-2(1H)-one derivative. Then, we carried a fine screening by molecular dynamics simulations, followed by free energy calculations. RESULTS: The best pharmacophore model created has five characteristics. Three hydrogen bonds acceptors (A) and two aromatic rings (R) make up AAARR (a sequential representation of chemical features of ligands). We have performed pharmacophore-based screening with different databases like Asinex, Chembridge, Lifechemicals, Maybridge, Specs, and Zinc. Top-scoring 30 molecules were considered for performing induced fit docking. Molecular Dynamics Simulations executed for the top five ligands confirmed that throughout the simulation, the protein-ligand complexes remained stable. CONCLUSION: Thus, the results obtained from this research provide insights for the development of oxazolo[4,5-g]quinazoline-2(1H)-one derivative as potent EGFR inhibitors.

Structure-based drug design of peroxisome proliferator-activated receptor gamma inhibitors: ferulic acid and derivatives.

Peroxisome proliferator-activated receptor gamma (PPARγ), ligand-activated transcription factor, is a key modulator of genes considered in diabetes development as well as treatment. Adipogenesis differentiation through PPARγ, CCAAT-enhancer protein alpha (C/EBPα) is identified as a critical mechanism in fat accumulation and weight gain. Polyphenols studied against adipocyte differentiation is taken up for consistent support and drug discovery. Structure-based drug design found useful to distinguish the underlying mechanism of receptor-ligand interaction and function. In this work, phenolic acids, ferulic acid and its derivatives are used as ligands. Molecular parameters have been set to filter and sort the 34 derivatives from ZINC and PubChem databases. Besides, for affinity and activity identification, troglitazone and resveratrol co-crystallized ligands have been studied. Absorption, distribution, metabolism, elimination and toxicity, density functional theory, highest occupied molecular orbital-lowest unoccupied molecular orbital values and docking scores define the drug candidate as a potential inhibitor. Residues Ser 342 and Arg 280 bind with the ligands by forming hydrogen bonds and hydrophobic contacts. Based on the docking score, pharmacophore properties and functional energy values of the top six compounds are chosen for molecular dynamics and simulation. Consistency and stability maintained throughout the simulation up to 50 ns were observed. Free binding energy values and standard deviation of receptor and ligand calculated using molecular mechanics-generalized Born and surface area solvation method (MM_GBSA) is found significant. Therefore, ferulic acid derivatives and phenolic acids could be a potential inhibitor for adipocyte differentiation and lipid accumulation.Communicated by Ramaswamy H. Sarma.

Importance of Fluctuating Amino Acid Residues in Folding and Binding of Proteins.

BACKGROUND: Conformational flexibility of proteins remains as one of the major events in protein-protein/DNA/ligand/small molecule binding to achieve its biological function in the cell. The availability of high-resolution structures of protein complexes is a valuable resource for researchers to understand the mechanisms behind such interactions and it is found that the flexibility of amino acid residues at binding sites is crucial for many important functions in the cell. METHODS: In this article, our statistical method (PreFRP) developed based on fluctuating amino acid residues and various amino acid indices related to flexibility/rigidity were used to study the importance of fluctuating amino acid residues in thermonucleases from pathogenic bacteria, cell penetrating peptides and intrinsically disordered proteins responsible for many neural disorders. RESULTS: The results from our analysis reveal the importance of fluctuating amino acid residues in folding and binding of proteins. The role of moderate and high fluctuating residues in themonucleases, cell penetrating peptide and disordered regions are discussed in detail. CONCLUSION: Therefore, our analysis will help in understanding the importance of fluctuating amino acid residues in proteins which undergo a conformation change phenomenon.

Prediction of kinase-inhibitor binding affinity using energetic parameters.

The combination of physicochemical properties and energetic parameters derived from protein-ligand complexes play a vital role in determining the biological activity of a molecule. In the present work, protein-ligand interaction energy along with logP values was used to predict the experimental log (IC50) values of 25 different kinase-inhibitors using multiple regressions which gave a correlation coefficient of 0.93. The regression equation obtained was tested on 93 kinase-inhibitor complexes and an average deviation of 0.92 from the experimental log IC50 values was shown. The same set of descriptors was used to predict binding affinities for a test set of five individual kinase families, with correlation values > 0.9. We show that the protein-ligand interaction energies and partition coefficient values form the major deterministic factors for binding affinity of the ligand for its receptor.