alexa Plasmodium vivax 1-deoxy-D-xylulose-5-phosphate synthase: HomologyModeling, Domain Swapping,and Virtual Screening | Open Access Journals
ISSN: 2153-0602
Journal of Data Mining in Genomics & Proteomics
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

Plasmodium vivax 1-deoxy-D-xylulose-5-phosphate synthase: HomologyModeling, Domain Swapping,and Virtual Screening

Divya Ramamoorthy, Sumit Handa, David J Merkler and Wayne C Guida*

Department of Chemistry, University of South Florida, USA

*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: [email protected]

Received Date: June 25, 2014; Accepted Date: July 30, 2014; Published Date: 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.

Visit for more related articles at Journal of Data Mining in Genomics & Proteomics


 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 first 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 refined 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.



Plasmodium; Homology modeling; Energy minimization; Active site; Domain swapping; Virtual screening


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, affecting about 2.4 billion people worldwide [3]. Although drugs are available to treat malaria, recurring antimicrobial resistance to the currently available drugs poses a significant threat to successful treatment. Discovering new molecular targets and new class of inhibitors are essential to overcome the issue of microbial resistance to drugs. The 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].

The first step involved in the NMP is formation of 1-deoxy-Dxylulose- 5-phosphate (DXP) by condensation of glyceraldehyde-3- phosphate (G3P) and pyruvate catalyzed by 1-deoxy-D- xylulose-5- phosphate synthase (DXS) [7]. The DXS enzyme has a thiaminebinding motif and requires TPP (thiamine pyrophosphate) and either a Mn2+ or Mg2+ divalent cation to manifest its activity [7]. DXS catalyzes the first 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. The 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. The 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 structures of DXS (from E. coli and D. radiodurans) have been reported to date [10]. The aligned structures were manually inspected for any anomalies and corrected to reflect the structurally conserved regions. Important regions from the alignment file are shown in (Figure 1). The regions shown in (Figure 1) represent the segment that connects the transit peptide to domain I, domain I - domain II linker region, and the domain II - domain III linker region. Alignment scores between the different species of DXS are shown in (Table 1).


Figure 1: Multiple alignment of DXS of P.knowlesi, P.vivax, P.falciparum, P.berghei, D.radiodurans, and E.coli, using ClustalW in the predicted domain linker regions; the consensus sequence characterizes identical residues as ‘*’, strongly similar residues as ‘:’ and weakly similar residues as ‘.’.

Homology model of PvDXS

The sequence of DXS P. vivax was obtained from NCBI protein sequence database, (, and it consists of 1111 residues. The sequence of PvDXS was then aligned with the sequences of previously resolved crystal structures for DXS, E. coli and D. radiodurans, and the alignment scores shown in (Table 1).

Sequence1 Sequence2 AlignmentScore
D.radiodurans P.berghei 28
D.radiodurans P.knowlesi 28
D.radiodurans P.vivax 29
E.coli P.knowlesi 29
D.radiodurans P. falciparum 30
E.coli P.berghei 30
E.coli P.vivax 30
E.coli P. falciparum 31
D.radiodurans E.coli 45
P. falciparum P.knowlesi 50
P. falciparum P.vivax 50
P.berghei P.vivax 56
P.berghei P.knowlesi 57
P. falciparum P.berghei 63
P.knowlesi P.vivax 74

Table 1: Alignment scores between different organisms of DXS.

Aligning the sequences and building the homology model:

Alignment of sequences is a crucial step in building a homology model to create a connection between the reference and the target proteins. Sequences should be properly aligned to ensure high quality of the model. Hence it is important to thoroughly inspect the sequences, especially in the conserved regions. Multiple sequence alignment of PvDXS with sequences of E. coli (PDB ID: 2O1S) [10], D. radiodurans (PDB ID: 2O1X) [10] and P. falciparum obtained from ClustalW 2.0.12 [9] are shown in (Figure 1). The aligned structures were manually inspected and edited to reflect the structurally conserved regions in the available crystal structures. The tertiary structure of the three proteins can be considered similar, since they share a significant degree of similarity, with a sequence identity of 30% and 29% with E. coli and D. radiodurans respectively. Relatively reliable homology models can be expected when the sequence identity between the template and the query sequence is 30% or greater [11]. In PvDXS, since the C- and N-termini are not likely to contribute significantly toward

ligand binding [12], some residues in these regions were truncated while building the model (Figure 2). The model generated for PvDXS has residues starting from 375 through 1011. Since templates were not available to model the starting sequence (residues ranging from 1-374), the model starts at residue 375. If the templates had gaps of more than 20 amino acid residues, the gaps were retained in the model. Thiamine pyrophosphate (TPP) and the divalent metal ion (Mg2+) were retained from the X-ray crystal structure of D. radiodurans, while generating the model. The initial model was generated using the PRIME software, available from Schrödinger, Inc. [13] and then subjected to energy minimization to produce a refined model for docking studies. MacroModel, also available from Schrödinger, Inc. [14-16], was used for geometry optimization and it relied upon the limited memory Broyden–Fletcher–Goldfarb–Shanno algorithm [13] for energy minimization with the OPLS 2005 Force Field. MacroModel minimization was performed for 500 iterations or until energy gradient convergence threshold of 0.1 kJ/mol/Å was obtained.


Figure 2: a: Homology model of PvDXS; b: Homology model of PkDXS. c: Homology model of PbDXS; d: Homology model of PfDXS. For all structures, TPP is shown with green carbon atoms.

Homology model of P. knowlesi, P. falciparum and P. berghei DXS:

The sequences of P. knowlesi, P. falciparum and P. berghei DXS were obtained from the NCBI. The sequence of P. knolwesi consists of 1122 residues, P. falciparum, 1205 residues, and P. berghei, 843 residues respectively. They were aligned with the sequences of E. coli and D. radiodurans as described earlier. The sequence of P. knowlesi has high homology to P. vivax than P. falciparum or P. berghei and P. falciparum has high homology to P. berghei. The models of P. knowlesi, P. falciparum and P. berghei were built using the aligned templates of D. radiodurans and E. coli; coordinates of TPP and the divalent metal cation, Mg2+ were retained from the D. radiodurans crystal structure.

Protein structure validation

The energy minimized structures were assessed for overall quality using PDBSum/ProCheck [17,18]. ProCheck is utilized to interrogate the stereochemical quality of a given protein structure by verifying the accuracy of parameters like bond angles, bond lengths, torsion angles and correctness of amino acid chirality. Using these criteria, the PvDXS model compares well with the available X-ray crystal structure of DrDXS and EcDXS.

An important indicator of the stereo chemical integrity of the model is the distribution of the main chain torsion angles: phi and psi, which can be examined using Ramachandran plots [17]. (Table 2) shows the Ramachandran plots and statistics of our homology models of Plasmodium DXS. The plots (Figure 3a) clearly show that the vast majority of the residues are in a phi-psi distribution consistent known secondary structure. The remaining residues that fall into the random conformation are small segments and are primarily present in the loop regions of the protein. For comparative purposes, Ramachandran plot statistics of E. coli and D. radiodurans DXS from the X-ray crystal structures are included in (Figure 3b). It is noteworthy that the homology model of PvDXS had 80.5% of total residues present in the favorable regions, while the disallowed regions contain about 1.4% of the residues.

PlotStatistics PvDXS PkDXS PfDXS PbDXS DrDXS   EcDXS
446 80.5% 463 78.3% 486 71.1% 450 81% 1592 84.9% 1580 91.40%
84 15.2% 99 16.8% 156 22.8% 78 14.2% 247 13.2% 132 7.60%
  16   2.9%   18   3.0%   23   3.4%   13   2.4%   19   1.0%   6     0.30%
8 1.4% 11 1.9% 19 2.8% 9 1.6% 17 0.9% 11 0.60%

Table 2: Statistics from Ramachandran plots.


Figure 3: (Top) Ramachandran plots of PvDXS and PkDXS; (Bottom) Ramachandran plots of PbDXS and PfDXS.

Active-site identity

Active-sites of the homology models of DXS generated were compared with the active-sites in the crystal structures of D. radiodurans DXS and E. coli DXS. It was found that the active-sites of the models were quite similar to the active sites relative to the templates used. A comparison of the residues in the active sites is tabulated in (Table 3). It is evident from (Table 3) that the active sites share a high degree of sequence identity/similarity. We also analyzed the structure for PKCphosphorylation sites and found that residues 27, 46, 75, 131, 148, 156, 162, 194, 231, 303, 438, 446, 621, 632, 679, 697, 790, 819 are prone to phosphorylation by Protein Kinase C. Residue 494 was identified to be prone to C-AMP phosphorylation.

Position D.radiodurans E.coli P. vivax P.knowlesi P.falciparum P.berghei
1 54:SER 52:SER 401:ALA 397:ALA 461:SER 182:PRO
2 80:VAL 78:VAL 469:ALA 423:ILE 487:ILE 208:ILE
3 82:HIS 80:HIS 471:HIS 425:HIS 489:HIS 210:HIS
4 83:GLN 81:GLN 472:SER 426:GLN 490:GLN 211:GLN
5 123:GLY 121:GLY 530:ARG 466:GLY 530:GLY 251:GLY
6 124:HIS 122:HIS 531:GLY 467:HIS 531:HIS 252:HIS
7 125:ALA 123:SER 532:GLY 468:SER 532:SER 253:SER
8 153:GLY 151:GLY 558:GLY 561:GLY 572:GLU 302:GLY
9 154:ASP 152:ASP 559:ASP 562:ASP 573:ARG 303:ASP
10 155:GLY 153:GLY 560:GLY 563:GLY 574:ILE 304:GLY
11 156:SER 154:ALA 561:GLY 564:GLY 575:PHE 305:GLY
12 181:ASN 179:ASN 586:ASN 589:ASN 655:ASN 330:ASN
13 183:ASN 181:ASN 588:ASN 591:ASN 657:ASN 332:ASN
14 185:MET 182:GLU 591:VAL 594:VAL 661:SER 333:ARG
15 186:SER XXX:XXXa 592:SER 595:SER 661:SER 304:GLY
16 187:ILE XXX:XXXa 593:LEU 596:LEU 662:LEU XXX:XXXa
17 289:LYS 284:LYS 681:LYS 702:LYS 751:LYS 426:LYS
18 304:HIS 288:TYR 696:HIS 717:ASP 773:ILE 430:PHE
19 347:PRO 344:PRO 778:PRO 779:PRO 853:PRO 516:PRO
20 348:ALA 345:ALA 779:ALA 780:ALA 854:ALA 517:ALA
21 349:MET 346:MSE 780:MET 781:MET 855:MET 518:MET
22 371:ILE 368:ILE 802:ILE 803:ILE 877:ILE 308:GLY
23 373:GLU 370:GLU 804:GLU 805:GLU 879:GLU 541:GLU
24 398:PHE 395:PHE 830:PHE 831:PHE 905:PHE 567:PHE
25 401:ARG 398:ARG 833:ARG 834:ARG 908:ARG 570:ARG
26 434:HIS 431:HIS 866:HIS 867:HIS 941:HIS 603:HIS

Table 3: Comparison of residues in the active-sites of DXS homology models and templates.


Structure of D. radiodurans and E. coli DXS

The crystal structure of D. radiodurans and E. coli DXS are both homo dimers, with each containing three distinct domains; domain I is located above domain II and domain III of the same monomer such that the active site is located within the same monomer, in the region between domain I and domain II. However, both of these crystal structures have missing residues in domain I. In E. coli DXS, the missing residues are found in not only in domain I (referred to as ‘segment I’ here) but also in the linker that connects domain I to domain II (referred to as ‘segment II’ here); the two missing segments were apparently the result of using a fungal protease during crystallization [10]. Residues in segment I of E. coli are present close to the active site. The crystal structure of D. radiodurans DXS was crystallized without the use of a fungal protease; it also has missing residues (199-243) in domain I in the region that connects strand 4 and 5 (segment I); however, residues present near the active site are ordered in this segment. The missing residues in segment I of D. radiodurans DXS (in spite of not using the fungal protease) might indicate that this region in domain I might be domain swapped such that residue 198 of one monomer is connected to residue 244 of the other monomer.

Structure of E. coli Transketolase

One of the closest structural homologues of DXS is Transketolase (TK), which catalyzes a similar biomolecular transformation. The crystal structure of TK from E. coli is also a homo dimer with three distinct domains. However, the arrangement of domains in TK differs substantially from DXS; domain I of one monomer is located above domain II and domain III of the other monomer such that the active site lies in the dimer interface region. The region that links domain I to domain II is larger in TK consisting of 95 residues. On the other hand, the linker region between domain I and domain II in DXS is comprised of only 20 residues [10]. The difference in domain arrangement between TK and DXS and the missing residues in DXS in the domain linker region might imply domain swapping in DXS where domain I of one monomer swaps partners with domain II of the other monomer such that the active site is shifted from the domain interface.

Domain swapping

Domain swapping is a phenomenon by which a bond is created between two or more protein molecules as their identical domains are exchanged to form an intertwined dimer or oligomer (Figure 4) [19]. Factors such as salt bridges and pH reveal important information regarding domain swapping [19]. The ability of a protein to domain swap can also be determined form the sequence by analyzing the sequence derived structure entropies of the residues. Usually domain swapping occurs in a hinge region of the protein, and often proline residues are present in the hinge regions that might increase the rigidity of the loop associated with domain swapping [20]. Domain swapping favors the entangling of polypeptide chains, which might change the native-state properties of the protein, like proteinase-resistance and toxicity [21]. However, domain swapping is often observed at unusually low pH(~4) and not generally at physiological pH [22].


Figure 4: Domain swapping in proteins.

In order to derive information about possible domain swapping in PvDXS, we analyzed the sequence for hinge regions, where swapping could potentially occur. We studied the sequence derived structure entropy for PvDXS. The sequence derived structure entropy (SDSE) values for the protein sequences were calculated using tri-peptides and tetra-peptides from different non-redundant databases as the standard using the Molecular Bioinformatics Center server [23]. The hinge regions were detected using DOMPRED [24] and DisEMBL [25], which indicated disorder in the regions: residues 1-250, residues 500- 550, 605-650 and around residue 727. The disordered regions based on loops/coils in the secondary structure [26] were checked on the DisEMBL server [25]. Our results indicate that residues 1-250 are highly disordered, which suggest that this part of the protein could be the signal/transit peptide [12]. Likewise, the sequence was checked for the presence of a signal peptide using the signalP server [27], which indicates that residues 1-25 form the signal peptide. Based on the above studies, PvDXS is predicted to have three domains, Domain I consisting of residues 250-582, domain linker region between residues 583-609, domain II consisting of residues 609-724 and domain III consisting of residues 725-1111. We predict that domain swapping could occur in PvDXS between residues 499-528 of domain I, which form the linker between strand 4 and 5 of domain I (Figure 5).


Figure 5: Disorder probability of PvDXS, derived from sequence.

We used the SDSE tool [23] from the Molecular Bioinformatics Center to generate the entropy based on sequence. This was performed to identify the plausible domain swap region. To confirm the region of domain swapping, the proline, histidine and isoleucine residues that lie in the disordered region of domain I and in the domain I - domain II linker region were mutated to alanine and the sequence derived structure entropy change was calculated; the results of which are shown in (Table 3). There was a huge gain in entropy for the Histidine residue His499 upon mutation to alanine, in the predicted swap region. As expected, the proline residues present in the hinge region had a loss of entropy when mutated to alanine, which suggests that it provide the rigidity associated with domain swap. Based on the results, it is evident that if domain swapping occurs, it most likely occurs in the region 499-594. Similarly, for P. knowlesi, the domain swap is predicted to occur between residues 586-612. For P. falciparum, the domain swap is predicted to occur between residues 653-678 and for P. berghei, between residues 327-353 respectively (Figure 6).


Figure 6: Homology model of PvDXS showing the residues in the predicted region of domain swapping. TPP shown with green carbon atoms.

Residues His499 and Pro500 are specific to P. knowlesi and P. vivax but absent in other Plasmodium species. Residue His510 is specific to PvDXS and is absent in all other Plasmodium species, indicating that this residue might play an important role as a gatekeeper in domain swapping. Salt bridges reveal important information regarding domain swapping [19]. Salt bridges were analyzed for the dimeric PvDXS structure using VMD [28]. Analysis revealed three salt bridges occurring in segment I of the dimer, connecting chain A and chain B; Asn486-His527, Asn518-His572 and Asn547-Lys706 respectively. The first salt bridge formed between Asn486 of Chain A and His527 of Chain B is interesting since this segment lies in the predicted domain swapped region. This salt bridge could be retained in the domain swapped dimer such that Asn486 of Chain A is connected to His 527 of the same chain after domain I is swapped between the residues 499-528, with Pro528 providing the necessary rigidity associated with domain swap. Similar observations are noted for P. knowlesi, P. berghei and P. falciparum (Table 4).

Residue Entropy Mutant Entropy DS
H499 0.87006 H499A 1.28247  0.412407
P500 1.39877 P500A 1.47198 0.073211
H510 1.38436 H510A 1.34371 -0.04065
P511 1.52913 P511A 1.40586 -0.12326
H527 1.38635 H527A 1.45683  0.070476
P528 1.4274 P528A 1.43547  0.008071
P540 1.44851 P540A 1.39533 -0.05318
I583 1.09052 I583A 1.1942 0.103685
I584 1.12959 I584A 1.29053 0.16094
P594 1.27088 P594A 1.45006 0.179181
P598 1.42308 P598A 1.39244 -0.03064
P605 1.28438 P605A 1.26844 -0.01594
I606 1.29282 I606A 1.4603 0.167478
I609 1.35446 I609A 1.47025 0.115785
H612 1.55882 H612A 1.40138 -0.15745
H614 1.39783 H614A 1.24602 -0.15181

Table 4: Sequence derived structure entropies for residues in the predicted domain swap region of PvDXS.

Structure of domain swapped PvDXS

To determine the structure of domain swapped PvDXS, comparative modeling was performed using E. coli Transketolase (PDB: 2R8O) as an additional template (along with E. coli DXS and D. radiodurans DXS); it had only 9% sequence identity with the sequence of PvDXS. The model was corrected for bond orders, bond angles, protonation states and then energy minimized using Schrodinger’s IMPACT module in the Protein Preparation Wizard. Later the prepared protein model was energy minimized employing MacroModel, using the LBFGS algorithm and the OPLS 2005 force field. The refined structure was validated using ProCheck. The refined model after energy minimization is shown in (Figure 7a). The refined structure had a score of 77.8% for the residues in the most favorable regions, 19.2% for residues in the additionally allowed regions, 1.7% for residues in generously allowed regions and 1.2% for residues in the disallowed regions (Figure 7c). In comparison to the unrefined structure, the residues in the most favorable regions have changed from 81.6% (Figure 7b) to 77.8% in the refined model (Figure 7c), but the residues in disallowed regions have changed from 2.2% (13 residues) to 1.2% (7 residues). Moreover, the residues in the disallowed regions were manually inspected for their vicinity to the active-site. It was found that these residues lie in the regions remote from the active- site. The above results suggest that the refined model may be a better one compared to the previous models to perform docking studies. As seen in (Figure 7b,7c) the phenyl ring of TPP is seen to occupy the region close to His510 and Pro511. Note that the side chains of the residues were slightly shifted using the transform tool of Maestro 8.5.2 prior to energy minimization, such that the residues no longer overlap with TPP


Figure 7a: Refined homology model of PvDXS based on E. coli Transketolase template; the regions shown in pink are the closed gaps. TPP shown with cyan carbon atoms.


Figure 7b: Active site in the initial model of PvDXS using E.coli Transketolase as one of the templates and the Ramachandran plot of the initial model. TPP carbon atoms are colored brown.


Figure 7c: Active site in the final model of PvDXS using E. coli Transketolase as one of the templates and the Ramachandran plot of the final model. TPP carbon atoms are colored cyan.

Active site identity: For the domain swapped PvDXS structure, the active site residues were compared with E. coli TK, D. radiodurans DXS and E. coli DXS. It was found that most of the residues are identical or similar with the active site of DXS as opposed to Transketolase (TK), as shown in (Table 5).

Position D.radioduransDXS P. vivaxdomain swapped DXS E.coliDXS E.coliTK
1 54:SER 401:ALA 52:SER 119:PRO
2 80:VAL 469:ALA 78:VAL XXX:XXXa
3 82:HIS 471:HIS 80:HIS 121:VAL
4 83:GLN 472:SER 81:GLN 121:VAL
5 109:PHE 516:PRO 107:PHE 9:ASN
6 123:GLY 530:ARG 121:GLY XXX:XXXa
7 124:HIS 531:GLY 122:HIS XXX:XXXa
8 125:ALA 532:GLY 123:SER XXX:XXXa
9 153:GLY 558:GLY 151:GLY 33:ILE
10 154:ASP 559:ASP 152:ASP 32:LEU
11 155:GLY 560:GLY 153:GLY 54:ILE
12 156:SER 561:GLY 154:ALA 50:SER
13 157:LEU 562:LEU 155:ILE 49:SER
14 181:ASN 586:ASN 179:ASN 35:TYR
15 183:ASN 588:ASN 181:ASN 31:LEU
16 185:MET 591:VAL 182:GLU 29:ALA
17 186:SER 592:SER XXX:XXXa 55:SER
18 187:ILE 593:LEU XXX:XXXa 55:SER
19 188:SER 594:PRO XXX:XXXa 56:GLY
20 289:LYS 681:LYS 284:LYS 27:ALA
21 347:PRO 778:PRO 344:PRO XXX:XXXa
22 348:ALA 779:ALA 345:ALA 56:GLY
23 349:MET 780:MET 346:MSE XXX:XXXa
24 371:ILE 802:ILE 368:ILE 53:ALA
25 373:GLU 804:GLU 370:GLU XXX:XXXa
26 395:TYR 827:TYR 392:TYR XXX:XXXa
27 398:PHE 830:PHE 395:PHE XXX:XXXa
28 401:ARG 833:ARG 398:ARG XXX:XXXa
29 434:HIS 866:HIS 431:HIS XXX:XXXa

Table 5: Comparison of residues in the active-sites of DXS homology models and templates.

Docking studies

Docking of TPP and the NCI Diversity Set compounds was performed using Schrodinger’s GLIDE software in order to validate the homology model(s) and the docked compounds were compared to the estimated absolute binding free energies of TPP and the NCI diversity set compounds docked to D. radiodurans DXS (reported here as GLIDE docking scores; only the lowest energy pose is reported).

After docking the NCI Diversity Set compounds, compound NSC659436 (5Z)-5-[[4-[(E)- (2,5-dioxoimidazolidin-4-ylidene) methyl]phenyl]methylidene]imidazolidine-2,4-dione was found to occupy putative TPP site in PvDXS and have a very favorable GLIDE docking score of -13.3 kcal/mol. Similarly, NSC659436 when docked to DrDXS had a docking score of -12.9 kcal/mol. TPP docked to PvDXS possessed a docking score of -14.1 kcal/mol and TPP when self-docked to DrDXS (PDB ID: 2O1X), exhibited a docking score of -13.4 kcal/mol. The GLIDE docking scores and poses (Figure 8) of TPP and NSC659436 docked to PvDXS (vs. DrDXS) suggest that our homology model can serve as a viable and predictive one for virtual screening. On the other hand, the docked poses of TPP and NSC659426 in the domain swapped model yielded docking scores for TPP and NSC659436 -5.51 and -5.38 kcal/mol respectively suggesting that our domain swapped structure, while interesting, may not be the biologically active form.


Figure 8: Structure of compound NSC659436; 8b. NSC659436 and TPP bound to PvDXR, Mg2+ cation is shown in pink.


In conclusion, we have generated homology models for P. vivax DXS and other Plasmodium species. We have predicted the probable regions of domain swapping in P. vivax DXS and have attempted to build the homology model based on the template of Transketolase for the putative domain swapped P. vivax structure. We have used energy minimization to refine our homology models. To validate our homology model, we have docked compounds from the NCI Diversity Set, from which NSC659436 (5Z)-5-[[4-[(E)-(2,5-dioxoimidazolidin-4- ylidene)methyl]phenyl]methylidene]imidazolidine-2,4-dione has a very favorable glide score of -13.7 kcal/mol. The docked pose of our virtual hit, NSC659436, is similar to the pose of the substrate (TPP), and exhibits interactions with PvDXS and DrDXS that are similar to the interactions observed for TPP.


Support from the Graduate Multidisciplinary Scholar (GMS) award by the Florida Center of Excellence for Bio molecular Identification and Targeted therapeutics (FCoE-BITT) to Sumit Handa is highly acknowledged. We thank the Florida Center of Excellence for Biomolecular Identification and Targeted therapeutics for the seed grant, No. GALS018, awarded to Dr. Wayne C. Guida and Dr. David J. Merkler.


Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Relevant Topics

Recommended Conferences

  • 9th International Conference on Bioinformatics
    October 23-24, 2017 Paris, France
  • 9th International Conference and Expo on Proteomics
    October 23-25, 2017 Paris, France

Article Usage

  • Total views: 11976
  • [From(publication date):
    October-2014 - Sep 24, 2017]
  • Breakdown by view type
  • HTML page views : 8156
  • PDF downloads :3820

Post your comment

captcha   Reload  Can't read the image? click here to refresh

Peer Reviewed Journals
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

[email protected]

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals


[email protected]

1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected].com

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

[email protected]

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001 Extn: 9042

© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version