The rapid spread of the Zika virus and its association with the abnormal brain development constitute a global health emergency. With a continuing spread of the mosquito vector, the exposure is expected to accelerate in the coming years. Despite number of efforts, there is still no proper vaccine or medicine to combat this virus. Of note, the NS2B-NS3 protein is proven to be the potential target for the Zika virus therapeutics. Hence, e-pharmacophore-based drug design strategy was employed to identify potent inhibitors of NS2B-NS3 protein from ASINEX database consisting of 467,802 molecules. A 3D e-pharmacophore model was generated using PHASE module of Schrödinger Suite. The generated model consists of one hydrogen bond acceptor (A), two hydrogen bond donors (D), and two aromatic rings (R), ADDRR. The model was further evaluated for its ability to screen actives using enrichment analysis. Subsequently, high-throughput virtual screening protocol was employed, and the resultant hit molecules were also examined for its binding free energies and ADME properties using Prime MM-GBSA and Qikprop module of Schrodinger packages, respectively. Finally, the screened hit molecule was subjected to molecular dynamics simulation to examine its stability. Overall, the results from our analysis suggest that compound BAS 19192837 could be a potent inhibitor for the NS2B-NS3 protein of the Zika virus. It is also noteworthy to mention that our results are in good agreement with literature evidences. We hope that this result is of immense importance in designing potential drug molecules to combat the spread of Zika virus in the near future.

Nalidixic acid is an antibiotic drug used for treatment of Salmonellosis, a gastrointestinal infection. DNA gyrase subunit A (GyrA) of Salmonella typhimurium is the drug target for nalidixic acid. Resistance of GyrA to nalidixic acid, because of a point mutation in S. typhimurium, was recently reported. Substitution of Phe in place of Ser at locus 83 in GyrA of S. typhimurium has been experimentally associated with nalidixic acid resistance. Despite recent efforts, the mechanism of this resistance is not well understood. In this investigation we used computational techniques to address this shortcoming. Our results showed that contact with residue Arg 91 is certainly important for efficient binding of nalidixic acid to the target protein, and that mutation of this residue results in 180° rotation of the antibiotic in its binding pocket, around its own long axis. It is hoped these findings may enable development of new antibiotics against resistant forms of Salmonella.

The emergence of nalidixic acid-resistant strains of Salmonella typhimurium remains to be a major public health problem. In particular, the substitution of Asn in place of Asp at the 87 loci in the GyrA of S. typhimurium was experimentally stated for nalidixic acid resistance. However, the data on the possible mechanism of nalidixic acid resistance are limited. In this study, I-Mutant2.0 and DUET program were employed to explore the impact of mutation on the stability of GyrA protein. Subsequently, molecular simulation techniques were employed to provide detailed information on the nalidixic acid-resistant associates with the D87N mutation in the GyrA of S. typhimurium. The binding free energy data depicts that nalidixic acid forms stable complex only with native-type GyrA than mutant (D87N) type GyrA protein. Moreover, our results theoretically suggest that hydrogen bonding formed by the Arg91 is certainly responsible for the GyrA of S. typhimurium drug selectivity. It is hoped that these evidences are immensely important for the development of new antibiotic and to overcome the nalidixic acid resistance in the near future.

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