Design and screening of syringic acid analogues as BAX activators-An in silico approach to discover "BH3 mimetics".

Although BAX, which is a molecular hit squad that incentive apoptosis was found to be an attractive emerging target for anticancer agents. The molecular mechanism of small molecules/peptides involved in the BAX activation was remain unknown. The present focus of the study is to identification and development of novel molecules which are precisely activates BAX mediated apoptosis. In this process we identified some syringic acid analogues associated with the BAX hydrophobic groove by a virtual-screen approach. Results from the docking studies revealed that, SA1, SA9, SA10, SA14 and SA21 analogues have shown good interaction with BAX trigger site, of which SA10 and SA14 bound specifically with Lys21 at α1 helix of BAX, a critical residue involved in BAX activation. All docking calculations of SA analogues were compared with clinically tested BH3 mimetics. In this entire in silico study, SA analogous have performed an ideal binding interactions with BAX compared to BH3 mimetics. Further, in silico point mutation of BAX-Lys21 to Glu21 resulted in structural change in BAX and showed reduced binding energy and hydrogen bond interactions of the selected ligands. Based on these findings, we propose that virtual screening and mutation analysis of BAX is found to be the critical advance method towards the discovery of novel anticancer therapeutics.

Design, synthesis, and evaluation of pyrazolo-pyrazole derivatives on Methylisocitratelyase of Pseudomonas aeruginosa: in silico and in vitro study.

Pseudomonas aeruginosa is an opportunistic micro-organism causing diseases both in animals and humans. In case of human pathology, the role of P. aeruginosa is one of the major concerns in intensive care septicemia. Presently, the drug resistance strains of P. aeruginosa are arising mainly by developing multiple mechanisms due to its natural and acquired resistance to many of the antimicrobial agents commonly used in clinical practice. As a result, there is a direct need to invent new drugs so that they may restrict the outbreak of multidrug resistant strains. Virtual high-throughput insilico screening, which helps to identify the chemical ligands that bind to the enzymes, is an important tool in drug discovery and the drugs discovered in this way are clinically tested. In this study, Methylisocitratelyase (MICL), which is essential for the survival of the bacterium and which doesn't show any similarity with the humans, was selected to evaluate the functions of high-affinity inhibitors (PPI-analogs) that are identified using the virtual screening approach. By adopting the computational analysis tools, structural, functional, and inhibitor interactions of MICL against P. aeruginosa were identified. The PPIA-32 is found to be the best binding interactions with MICL. PPIA-32 reduces the binding affinity for substrate to residues required for MICL enzyme activity and also Root Mean Square Deviation simulations show the most stable nature of PPA32-MICL(complex) than that of MICL alone, thereby effectively inhibiting the growth of virulent P. aeruginosa. To our surprise, the same phenomenon is also identified with other gram-negative bacteria like Escherichia coli, Klebsiella pneumoniae, and Salmonella typhi.

Molecular modeling and docking studies of O-succinylbenzoate synthase of M. tuberculosis--a potential target for antituberculosis drug design.

Menaquinone is a lipid-soluble naphthoquinone that is essential for various pivotal functions of bacteria. Naphthoquinone is synthesized from chorismate of the shikimate pathway in microorganisms. Due to its absence in humans and animals, menaquinone biosynthesis has been an attractive target for development of antibiotics against a number of important microbial pathogens, such as Mycobacterium tuberculosis (Mtb). In shikimate pathway, O-succinylbenzoate synthase (OSBS) plays a major role and is one of the major potential drug targets. For Mtb-OSBS, a systematic study was conducted to get an insight about Mtb-OSBS enzyme and the corresponding inhibitors using in silico methods. The 3-D model of Mtb-OSBS was built using structure coordinates of Thermobifida fusca. O-succinylbenzoate synthase, the model, was further refined. The active site amino acids have been identified by comparing the template sequence with the Mtb-OSBS sequence. We identified that Lys(108), Asn(140), Asp(138), Lys(110), Glu(189), Ser(236), Asp(188), Arg(27), Tyr(52), and Ser(237) are highly conserved, and these may play a vital role as active residues, similar to that in template protein. As per the competitive binding of substrate (2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC)), we screened the SHCHC through AutoDock 4.0. The SHCHC molecule was further modified structurally and optimized through PRODRG server. Docking of the 12 lead molecules for best interactions with Mtb-OSBS has given an insight that all the lead molecules have shown interactions with active site amino acids of Mtb-OSBS. MD simulation analysis report has shown the stable conformation annotations of Mtb-OSBS. These hypothetical studies create another way to develop more potential drugs against the deadly mycobacterium.

Design and evaluation of new chemotherapeutics of aloe-emodin (AE) against the deadly cancer disease: an in silico study.

The Bcl-2 family proteins include pro- and antiapoptotic factors acting as critical arbiters of apoptotic cell death decisions in most circumstances. Evasion of apoptosis is one of the hallmarks of cancer, relevant to tumorigenesis as well as resistance to cytotoxic drugs, and deregulation of Bcl-2 proteins was observed in many cancers. Since Bax-mediated induction of apoptosis is a crucial mechanism in cancerous cells, we aimed at conducting in silico analysis on Bax in order to predict the possible interactions for anticancer agents. The present report depicts the binding mode of aloe-emodin and its structurally modified derivatives onto Bax. The structural information about the binding site of Bax for docked compounds obtained from this study could aid in screening and designing new anticancer agents or selective inhibitors for chemotherapy against Bax.