Open Access Research Article J Data Mining Genomics Proteomics Algorithm Evaluation and Validation in Proteomics ISSN:2153-0602 JDMGP an open access journal Keywords: Plasmodium; Homology modeling; Energy minimization; Active site; Domain swapping; Virtual screening Introduction Biochemical processes that exist in bacteria, but not in humans, provide a useful way to develop novel inhibitors to combat diseases. One such pathway is the Non-Mevalonate Pathway (NMP) exclusively present in lower animals and bacteria, which is utilized to synthesize isoprenoids for terpene biosynthesis [1]. Isopentenyl diphosphate (IPP) and Di methyl Allyl phosphate (DMAPP) are the end products of this pathway and serve as precursors for the biosynthesis of various terpenoids including cholesterol and vitamin E [2]. Since higher animals utilize the mevalonate pathway for isoprenoid biosynthesis, the NMP is an attract ive biochemical pathway, the enzymes of which provide several targets for the discovery of anti-infectious therapeutic agents. Among the infectious diseases, malaria ranks highest, afecting about 2.4 billion people worldwide [3]. Although drugs are available to treat malaria, recurring antimicrobial resistance to the currently available drugs poses a signifcant threat to successful treatment. Discovering new molecular targets and new class of inhibitors are essential to overcome the issue of microbial resistance to drugs. Te apicoplast, a non-photosynthetic plastid found in Plasmodium, is nuclear encoded [1] and is necessary to the survival of the malaria parasite [4]; it harbors many pathways including the NMP [5]. Since the non-mevalonate pathway is present in all intra-erythrocytic stages of Plasmodium, it represents an extremely attractive target for antimalarial drug discovery and development. Major causative agents of malaria include Plasmodium vivax, Plasmodium falciparum, Plasmodium berghei, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi, out of which Plasmodium falciparum and Plasmodium vivax are most important for pathogenesis of the disease [6]. Plasmodium falciparum is deadly while Plasmodium vivax causes less severe complications but is more widespread, especially in temperate zones. Moreover, Plasmodium vivax can hibernate in the liver for months or years and can resurface, causing disease [6]. Te frst step involved in the NMP is formation of 1-deoxy-D- xylulose-5-phosphate (DXP) by condensation of glyceraldehyde-3- phosphate (G3P) and pyruvate catalyzed by 1-deoxy-D- xylulose-5- phosphate synthase (DXS) [7]. Te DXS enzyme has a thiamine- binding motif and requires TPP (thiamine pyrophosphate) and either a Mn 2+ or Mg 2+ divalent cation to manifest its activity [7]. DXS catalyzes the frst step of the NMP, which is also the rate limiting step. Formation of DXP is not a committed step of the non mevalonate pathway as DXS is also essential for thiamine and pyridoxal biosynthesis [8], thus making it an alluring target to develop drugs for anti-infectious diseases. By targeting enzymes present in the NMP for inhibition, the DXS enzyme in either P. falciparum or could potentially lead to the development of potent curative agents for malaria and other infectious diseases. To better understand the structural components of DXS, a crystal structure would be valuable. Te only crystal structures available for this enzyme to date are from E. coli and D. radiodurans. Here, we present homology models for P. vivax and other Plasmodium species (P. falciparum, P. berghei) of DXS in order to comprehend its structural features and for use in virtual screening of compound libraries readily available from the National Cancer Institute and other sources. Methods and Results Comparative modeling generates a 3-D structure of an enzyme based on previously determined X-ray crystal structures. Te sequence of PvDXS and other Plasmodium DXS were obtained from PUBMED and were aligned with the sequences of E. coli and D. radiodurans, the available crystal structures for DXS using ClustalW [9]. Two crystal *Corresponding author: Wayne C Guida, Professor, Department of Chemistry, University of South Florida, 4202 E fowler Avenue, Tampa, Fl 33620, USA, Tel: 727- 452-2986; E-mail: wguida@usf.edu Received June 25, 2014; Accepted July 30, 2014; Published August 08, 2014 Citation: Ramamoorthy D, Handa S, Merkler DJ, Guida WC (2014) Plasmodium vivax 1-deoxy-D-xylulose-5-phosphate synthase: Homology Modeling, Domain Swapping, and Virtual Screening. J Data Mining Genomics Proteomics S1:003. doi:10.4172/2153-0602.S1-003 Copyright: © 2014 Ramamoorthy D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Plasmodium vivax 1-deoxy-D-xylulose-5-phosphate synthase: Homology Modeling, Domain Swapping, and Virtual Screening Divya Ramamoorthy, Sumit Handa, David J Merkler and Wayne C Guida* Department of Chemistry, University of South Florida, USA Abstract Structure-based computational approaches are needed to model proteins in the absence of any crystal structures and identify protein-ligand interactions. Biochemical pathways that exist in microorganisms but absent in humans serve as excellent targets for antimicrobial drug design. The Non-Mevalonate Pathway (NMP) is one such pathway that is present in all intra-erythrocytic stages of Plasmodium and could serve as a target for anti-malarial drug design and development. The frst enzyme of the pathway, DXS (1-deoxy-D-xylulose-5-phosphate synthase) is the rate limiting enzyme and is also important for the biosynthesis of pyridoxal and thiamine. In the absence of available crystal structures, our aim was to develop homology models for Plasmodium DXS, which could provide insight into the structural features of this enzyme and its likely binding to ligands. Initial models were built using the PRIME module of Schrödinger Suite 2010 and then refned using MacroModel energy minimization. Analyses were also carried out using bioinformatics tools to predict domain swapping in Plasmodium DXS. This study should prove useful in the design and development of novel anti-malarial therapeutics. Journal of Data Mining in Genomics & Proteomics J o u r n a l o f D a t a M i n i n g i n G e n o m i c s & P r o t e o m i c s ISSN: 2153-0602 Ramamoorthy et al., J Data Mining Genomics Proteomics 2014, S1 DOI: 10.4172/2153-0602.S1-003