Molecular modelling studies in explaining the higher GPVI antagonistic activity of the racemic 2-(4-methoxyphenylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide than its enantiomers^$

<p>The GPVI receptor on the platelets plays a major role in inhibiting arterial thrombosis with limited risk of bleeding and is considered a potential anti-thrombotic target for arterial thrombosis. In the reported anti-thrombotics, tetrahydropyridoindoles, the title compound was the best inhibitor of the collagen mediated platelet aggregation by antagonizing the platelet receptor GPVI. Interestingly, the racemic title compound showed better antagonism (IC₅₀ racemate = 6.7 μM) than either of its enantiomers (IC₅₀ <i>S</i> enantiomer = 25.3 μM; IC₅₀ <i>R</i> enantiomer = 126.3 μM). In order to explain this, the molecular modelling approaches <i>viz</i>. site map analysis, protein–protein docking and molecular dynamics simulation were carried out, which led to the identification of a second binding site located near the primary antagonist binding site known to bind losartan. The induced fit docking studies for both the enantiomers at the primary and secondary binding sites showed that the <i>S</i>-enantiomer has better interactions at the primary binding site than the <i>R</i>-enantiomer, while the <i>R</i>-enantiomer has better interactions at the secondary site than the <i>S</i>-enantiomer. Hence, the overall interactions of the racemic compound containing equimolar mixture may be higher than any one of the enantiomers and may explain the higher activity than its enantiomers of the racemic compound.</p

Combinatorial design and virtual screening of potent anti-tubercular fluoroquinolone and isothiazoloquinolone compounds utilizing QSAR and pharmacophore modelling^$

<p>The virulence of tuberculosis infections resistant to conventional combination drug regimens cries for the design of potent fluoroquinolone compounds to be used as second line antimycobacterial chemotherapeutics. One of the most effective in silico methods is combinatorial design and high throughput screening by a ligand-based pharmacophore prior to experiment. The combinatorial design of a series of 3850 fluoroquinolone and isothiazoloquinolone compounds was then screened virtually by applying a topological descriptor based quantitative structure activity relationship (QSAR) for predicting highly active congeneric quinolone leads against <i>Mycobacterium fortuitum</i> and <i>Mycobacterium smegmatis</i>. The predicted highly active congeneric hits were then subjected to a comparative study between existing lead sparfloxacin with fluoroquinolone FQ hits as well as ACH-702 with predicted active isothiazoloquinolones, utilizing pharmacophore modelling to focus on the mechanism of drug binding against mycobacterial DNA gyrase. Finally, 68 compounds including 34 FQ and 34 isothiazoloquinolones were screened through high throughput screening comprising QSAR, the Lipinski rule of five and ligand-based pharmacophore modelling.</p

Insight into the Mechanism of Decontamination and Disinfection at the Functionalized Carbon Nanotube–Polymer Interfaces

The role of different functional groups and the nature of the functional group on multiwalled carbon nanotube (MWCNT) surface were thoroughly studied for silver nanoparticles (AgNPs) loading and on the mechanism of decontamination and disinfection. The surfactant free method for grafting of AgNPs on MWCNT surface followed by vacuum annealing was adapted to enhance the interfacial interactions of nanomaterials with bacteria. The best performing functionalized MWCNT was selected for the fabrication of functional composite membrane for further insight into the interfacial interaction of polymer–nanomaterials. It has been shown that at an optimized weight percentage loading of functionalized MWCNTs, nanotube scaffolds were generated inside the pores of polysulfone membrane to sieve out toxic metal ions and bacteria by physical and chemical elimination without compromising the flux rate of filtration. The structure property relationship of the nanocomposite membrane has been thoroughly evaluated by the morphological, surface area, and contact angle measurement studies. The modified surface of MWCNTs by Ag nanoparticles and polar functional groups placed on the pores of the membrane was thus further exposed for interfacial interaction with the decontaminated and disinfected water, which in turn enhances the efficiency of filtration

Enhanced Anticancer Potential of Encapsulated Solid Lipid Nanoparticles of TPD: A Novel Triterpenediol from <i>Boswellia serrata</i>

A pentacyclic triterpenediol (TPD) from <i>Boswellia serrata</i> has significant cytotoxic and apoptotic potential in a large number of human cancer cell lines. To enhance its anticancer potential, it was successfully formulated into solid lipid nanoparticles (SLNs) by the microemulsion method with 75% drug entrapment efficiency. SEM and TEM studies indicated that TPD-SLNs were regular, solid, and spherical particles in the range of 100–200 nm, and the system indicated that they were more or less stable upon storing up to six months. TPD loaded SLNs showed significantly higher cytotoxic/antitumor potential than the parent drug. TPD-SLNs have 40–60% higher cytotoxic and apoptotic potential than the parent drug in terms of IC₅₀, extent of apoptosis, DNA damage, and expression of pro-apoptotic proteins like TNF-R1, cytochrome-<i>c</i>, and PARP cleavage in HL-60 cells. Moreover, blank SLNs did not have any cytotoxic effect on the cancer as well as in normal mouse peritoneal macrophages. The <i>in vivo</i> antitumor potential of TPD-SLNs was significantly higher than that of TPD alone in Sarcoma-180 solid tumor bearing mice. Therefore, SLNs of TPD successfully increased the apoptotic and anticancer potential of TPD at comparable doses (both <i>in vitro</i> and <i>in vivo)</i>. This work provides new insight into improvising the therapeutic efficacy of TPD by adopting novel delivery strategies such as solid lipid nanoparticles