Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK)

Abstract

BackgroundDue to the widespread abusage of antibiotics, antibiotic-resistance in Streptococcus pneumoniae (S. pneumoniae) has been increasing quickly in recent years, and it is obviously urgent to develop new types of antibiotics. Two-component systems (TCSs) are the major signal transduction pathways in bacteria and have emerged as potential targets for antibacterial drugs. Among the 13 pairs of TCSs proteins presenting in S. pneumoniae, VicR/K is the unique one essential for bacterium growth, and block agents to which, if can be found, may be developed as effective antibiotics against S. pneumoniae infection.ResultsUsing a structure-based virtual screening (SBVS) method, 105 compounds were computationally identified as potential inhibitors of the histidine kinase (HK) VicK protein from the compound library SPECS. Six of them were then validated in vitro to be active in inhibiting the growth of S. pneumoniae without obvious cytotoxicity to Vero cell. In mouse sepsis models, these compounds are still able to decrease the mortality of the mice infected by S. pneumoniae and one compound even has significant therapeutic effect.ConclusionTo our knowledge, these compounds are the first reported inhibitors of HK with antibacterial activity in vitro and in vivo, and are novel lead structures for developing new drugs to combat pneumococcal infection.

Computational Methods in Drug Discovery

“…SB-vHTS has been used successfully in identifying novel and potent hits in several drug discovery campaigns Lu et al, 2006;Zhao et al, 2006;Ruiz et al, 2008;Triballeau et al, 2008;Li et al, 2009;Budzik et al, 2010;Izuhara et al, 2010;Simmons et al, 2010;Roughley et al, 2012). We discuss two examples in which SB-vHTS played pivotal role in discovery of lead compounds.…”

Template-Based Protein Modeling: Recent Methodological Advances

“…A recent review has discussed the current trends and applications of homology modeling in the drug discovery process. [134] Various recent applications of homology modeling in the drug discovery process include lead identification,[135, 136] lead optimization, understanding of selectivity,[137] explanation of resistance development,[138] binding site analysis and mutation studies. [139] An example is for the histidine kinase (HK) VicK protein, which is essential for bacterial growth in S. pneumoniae.…”

Virtual Screening Strategies: A State of Art to Combat with Multiple Drug Resistance Strains

“…Nan Li et al [74] screened the SPECS compound library by using structural based virtual screening to identify the potential inhibitors of the histidine kinase (HK) VicK protein from S. pneumonia. Based on molecular diversity, shape complementarities, and the potential to form hydrogen bonds and hydrophobic interactions in the binding pocket, they identified a series of 105 compounds.…”