Evaluation of xanthene-appended quinoline hybrids as potential leads against antimalarial drug targets.

A series of fused heterocycle xanthene-appended quinoline 6a-n was successfully synthesized with regioselectivity and characterized using IR, 1H NMR, 13C NMR, and mass spectral data. Molecular docking was performed to find the binding efficacy of all these newly synthesized compounds towards thirteen antimalarial drug targets. Molecular dynamics simulation was carried out to predict the stability of the ligand-bound complex in a solvent medium. Blind and site-directed docking with compounds 6a-n against 13 drug targets revealed most of the ligands to have a good binding affinity with the targets. Analysis on the basis of binding energy, binding modalities of the ligands, intermolecular interactions, and pharmacophore, we identified only one of the ligand-receptor complexes to provide better results. Molecular dynamic simulation of the selected receptor-ligand complex revealed that the synthesized compound had a better binding affinity with the receptor than the native ligand complex. Further analysis of the synthesized ligand in the laboratory may prove promising results in the search for potential antimalarial drugs.

Evaluation of peptide designing strategy against subunit reassociation in mucin 1: A steered molecular dynamics approach.

Subunit reassociation in mucin 1, a breast cancer tumor marker, is reported as one of the critical factors for its cytoplasmic activation. Inhibition of its heterodimeric association would therefore result in loss of its function and alter disease progression. The present study aimed at evaluating peptide inhibitor designing strategies that may serve as antagonist against this receptor-ligand alliance. Several peptides and their derivatives were designed based on native residues, subunit interface, hydrogen bonding and secondary structure. Docking studies with the peptides were carried on the receptor subunit and their binding affinities were evaluated using steered molecular dynamics simulation and umbrella sampling. Our results showed that among all the different classes of peptides evaluated, the receptor based peptide showed the highest binding affinity. This result was concurrent with the experimental observation that the receptor-ligand alliance in mucin 1 is highly specific. Our results also show that peptide ligand against this subunit association is only stabilized through native residue inter-protein interaction irrespective of the peptide structure, peptide length and number of hydrogen bonds. Consistency in binding affinity, pull force and free energy barrier was observed with only the receptor derived peptides which resulted in favorable interprotein interactions at the interface. Several observations were made and discussed which will eventually lead to designing efficient peptide inhibitors against mucin 1 heterodimeric subunit reassociation.

Systematic prioritization of functional hotspot in RIG-1 domains using pattern based conventional molecular dynamic simulation.

BACKGROUND: Retinoic acid inducible gene 1 (RIG-1), multi-domain protein has a role-play in detecting viral nucleic acids and stimulates the antiviral response. Dysfunction of this protein due to mutations makes the route vulnerable to viral diseases. AIM: Identification of functional hotspots that maintains conformational stability in RIG-1 domains. METHODS: In this study, we employed a systematic in silico strategy on RIG-1 protein to understand the mechanism of structural changes upon mutation. We computationally investigated the protein sequence signature for all the three domains of RIG-1 protein that encloses the mutation within the motif. Further, we carried out a structural comparison between RIG-1 domains with their respective distant orthologs which revealed the minimal number of interactions required to maintain its structural fold. This intra-protein network paved the way to infer hotspot residues crucial for the maintenance of the structural architecture and folding pattern. KEY FINDINGS: Our analysis revealed about 40 hotspot residues that determine the folding pattern of the RIG-1 domains. Also, conventional molecular dynamic simulation coupled with essential dynamics provides conformational transitions of hot spot residues among native and mutant structures. Structural variations owing to hotspot residues in mutants again confirm the significance of these residues in structural characterization of RIG-1 domains. We believe our results will help the researchers to better comprehend towards regulatory regions and target-binding sites for therapeutic design within the pattern recognition receptor proteins. SIGNIFICANCE: Our protocol employed in this work describes a novel approach in identifying signature residues that would provide structural insights in protein folding.

Casting the critical regions in nucleotide binding oligomerization domain 2 protein: a signature mediated structural dynamics approach.

Nucleotide binding oligomerization domain 2 (NOD2), a protein involved in the first line defence mechanism has a pivotal role in innate immunity. Impaired function of this protein is implicated in disorders such as Blau syndrome and Crohn's disease. Since an altered function is linked to protein's structure, we framed a systematic strategy to interpret the structure-function relationship of the protein. Initiated with mutation-based pattern prediction and identified a distant ortholog (DO) of NOD2 from which the intra-residue interaction network was elucidated. The network was used to identify hotspots that serve as critical points to maintain the stable architecture of the protein. Structural comparison of NOD2 domains with a DO revealed the minimal number of intra-protein interactions required by the protein to maintain the structural fold. In addition, the conventional molecular dynamics simulation emphasized the conformational transitions at hot spot residues between native NOD2 domains and its respective mutants (G116R, R42W and R54A) structures. The analysis of intra-protein interactions globally and the displacement of residues locally around the mutational site revealed loss of several critical bonds and residues vital for the protein's function. Conclusively we report, about 10 residues in leucine-rich repeat, 13 residues in NOD and 6 residues in CARD domain are required by the NOD2 to maintain its function. This protocol will help the researchers to achieve for more prospective studies to attest druggable site utility in discovering novel drug candidates.