Editorial [Hot Topic: In Silico (Guest Editor: Alexandre G. de Brevern)]

Coming from Crimea, the Black Death spread to Western Europe and North Africa during the 1340s. From 1346 to 1352, the plague killed an estimated 25-40% of Europeans of all age-groups [1], i.e. 30 to 60% of Europe population. One of the earliest and most widely accepted explanations was that God was punishing humanity for their sins. One remedy for the curse was to do penitence. Thus in 1348 there rapidly arose a mass movement of flagellation [2]. In fact flagellation could not really help against such threat. The Black Death or Bubonic plague is caused by Yersinia pestis, a Eubacteria discovered in 1894 by Alexandre Yersin. It is transmitted by the bite of the flea Xenopsylla cheopsis. This flea lives by feeding the blood of many species besides man but its most preferred relationship is with the black rat (Rattus rattus). Fossilized remains of the plague flea have been found in large numbers in Amarna, Egypt [3, 4] about 1350 BC, and thus could be directly linked to the events described in the Book of Samuel [5, 6]. During the epidemic of Bubonic plague in London in 1665-1666, the known treatments were made use of, e.g. the so-famous Theriac or Venice Treacle which is used from the time of ancient Rome as a remedy against poison [7]. Since then, more specialized and novel treatments have been developed. However, since the characterization of Yersinia pestis, numerous drugs have been developed against it, e.g. gentamicin or doxycycline [8]. These researches had been carried out using more elaborated biochemical, biophysical and biological approaches. However, with the explosion of genomic sequencing -815 complete genomes are made available for the scientific community (as of January 2009) [9]- complementing the experimental information with the increasing power of computational facilities has given new opportunities to fight against infectious diseases and to identify pertinent drug targets with novel methodologies. The in silico approaches have been playing a prominent role in this research area during the last decade. This special issue presents the various views about the different in silico approaches by some of the best international research teams. Pr. Sowdhamini's group has compared different genomes from a group of enterobacteric pathogens known to share similar genomic content but having diverse host specificities and distinct disease symptoms [10]. The detailed cross-genome analysis of these subspecies provides an understanding of the diversity and unique attributes defined in the individual Salmonella enterica genomes. Pr. Srinivasan's group develops new approaches dedicated to Plasmodium falciparum analysis, the most important causative agent of malaria [11]. The latter has a very specific genome and thus needs to be studied thoroughly and specifically. They present examples of protein-protein interactions across human and P. falciparum, potentially happening during pathogenesis. Pr. Deleage's work deals with Hepatitis C Virus (HCV). They have developed the European Hepatitis C Virus Database (euHCVdb, http://euhcvdb.ibcp.fr/), a collection of relevant structural models that can help in drug design , with strategies for combating resistance to drug treatment and to have a better understanding structural biology of the HCV [12]. They present some examples of the use of the database. Within this new research field, an important axis of research concerns the transmembrane proteins, they represent about ∼25% of proteins coded by genomes. Moreover, they serve as targets for about 2/3rd of the marketed drugs out of which 50% specifically target a GPCR [13]. As these proteins are embedded in a lipid membrane that constitutes a very specific environment, they represent only about ∼1% of all the available structures, owing to the difficulties associated with their crystallization [14]. Thus alternative approaches are required to obtain structural information. Consequently methods aiming at constructing 3D structural models are becoming an important area of research, for understanding biological mechanisms and interactions [15]. Wang and Duan summarizes the recent computational researches done on CCchemokine receptor 5 (CCR5), an essential co-receptor for HIV entry into the cells and show how the recently solved GPCR structures would provide new insights into the modeling of CCR5-inhibitor binding [16]. Pr. Etchebest's group work focus on an unorthodox chemokine receptor, named DARC, which binds chemokines of both CC and CXC classes and do not couple to G proteins and activate their signaling pathways. DARC had also been associated to cancer progression, numerous inflammatory diseases, and possibly to AIDS. We show our recent development of the construction and analyzes of structural models of DARC [17]. We underline the difficulty to propose pertinent structural models of transmembrane protein using comparative modeling process, and also highlight the use of other dedicated approaches like the analysis using Protein Blocks [18-20]. Finally, we present the recent development of protein - protein docking carried out between DARC structural models and CXCL-8 structures using an innovative hierarchal search procedure, based on both rigid and flexible docking [21].