Homology modeling and docking of AahII-Nanobody complexes reveal the epitope binding site on AahII scorpion toxin.

Scorpion envenoming and its treatment is a public health problem in many parts of the world due to highly toxic venom polypeptides diffusing rapidly within the body of severely envenomed victims. Recently, 38 AahII-specific Nanobody sequences (Nbs) were retrieved from which the performance of NbAahII10 nanobody candidate, to neutralize the most poisonous venom compound namely AahII acting on sodium channels, was established. Herein, structural computational approach is conducted to elucidate the Nb-AahII interactions that support the biological characteristics, using Nb multiple sequence alignment (MSA) followed by modeling and molecular docking investigations (RosettaAntibody, ZDOCK software tools). Sequence and structural analysis showed two dissimilar residues of NbAahII10 CDR1 (Tyr27 and Tyr29) and an inserted polar residue Ser30 that appear to play an important role. Indeed, CDR3 region of NbAahII10 is characterized by a specific Met104 and two negatively charged residues Asp115 and Asp117. Complex dockings reveal that NbAahII17 and NbAahII38 share one common binding site on the surface of the AahII toxin divergent from the NbAahII10 one's. At least, a couple of NbAahII10 - AahII residue interactions (Gln38 - Asn44 and Arg62, His64, respectively) are mainly involved in the toxic AahII binding site. Altogether, this study gives valuable insights in the design and development of next generation of antivenom.

In vitro efficacy and in silico analysis of cefixime-ofloxacin combination for Salmonella Typhi from bloodstream infection.

AIMS: Recently, the cefixime-ofloxacin combination is approved by Drug Controller General of India to treat typhoid fever. We sought to evaluate the antimicrobial activity of cefixime-ofloxacin combination against Salmonella Typhi. METHODS AND RESULTS: A total of 283 nonduplicate S. Typhi isolates collected during 2012-2014 were included in this study. Minimum inhibitory concentration (MIC) of cefixime and ofloxacin was determined by using broth microdilution method. Combinational testing was performed by using checkerboard assay. In checkerboard assay, synergistic activity was seen in 11% of isolates, while the majority of the isolate showed indifference and none of them showed antagonism. An in silico strategy, an alternative to the animal model, was carried out to understand drug interaction and toxicity. Molecular docking results elucidated that cefixime and ofloxacin are capable of inhibiting the cell wall synthesis and DNA replication, respectively. Computational ADMET analysis showed no toxicity and no drug-drug interaction between cefixime and ofloxacin. CONCLUSION: Cefixime-ofloxacin combination could be effective against moderately susceptible fluoroquinolone S. Typhi but not fluoroquinolone-resistant isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: Cefixime-ofloxacin combination with no drug-drug interaction and nontoxic predicted through computational analysis did not show antagonism against S. Typhi in in vitro. Although this study showed no adverse effects with the cefixime-ofloxacin combination, further studies on pharmacokinetic and pharmacodynamic (PK-PD) parameters of cefixime and ofloxacin combination are warranted.

Ion pairs in non-redundant protein structures.

Ion pairs contribute to several functions including the activity of catalytic triads, fusion of viral membranes, stability in thermophilic proteins and solvent-protein interactions. Furthermore, they have the ability to affect the stability of protein structures and are also a part of the forces that act to hold monomers together. This paper deals with the possible ion pair combinations and networks in 25% and 90% non-redundant protein chains. Different types of ion pairs present in various secondary structural elements are analysed. The ion pairs existing between different subunits of multisubunit protein structures are also computed and the results of various analyses are presented in detail. The protein structures used in the analysis are solved using X-ray crystallography, whose resolution is better than or equal to 1.5 A and R-factor better than or equal to 20%. This study can, therefore, be useful for analyses of many protein functions. It also provides insights into the better understanding of the architecture of protein structure.