Vascular wilt of tomato caused by Fusarium oxysporum f.sp. lycopersici (FOL) is one of the most devastating diseases, that delimits the tomato production worldwide. Fungal short-chain dehydrogenases/reductases (SDRs) are NADP(H) dependent oxidoreductases, having shared motifs and common functional mechanism, have been demonstrated as biochemical targets for commercial fungicides. The 1,3,6,8 tetra hydroxynaphthalene reductase (T4HNR) protein, a member of SDRs family, catalyzes the naphthol reduction reaction in fungal melanin biosynthesis. We retrieved an orthologous member of T4HNR, (complexed with NADP(H) and pyroquilon from Magnaporthe grisea) in the FOL (namely; FOXG_04696) based on homology search, percent identity and sequence similarity (93% query cover; 49% identity). The hypothetical protein FOXG_04696 (T4HNR like) had conserved T-G-X-X-X-G-X-G motif (cofactor binding site) at N-terminus, similar to M. grisea (1JA9) and Y-X-X-X-K motif, as a part of the active site, bearing homologies with two fungal keto reductases T4HNR (M. grisea) and 17-β-hydroxysteroid dehydrogenase from Curvularia lunata (teleomorph: Cochliobolus lunatus PDB ID: 3IS3). The catalytic tetrad of T4HNR was replaced with ASN115, SER141, TYR154, and LYS158 in the FOXG_04696. The structural alignment and superposition of FOXG_04696 over the template proteins (3IS3 and 1JA9) revealed minimum RMSD deviations of the C alpha atomic coordinates, and therefore, had structural conservation. The best protein model (FOXG_04696) was docked with 37 fungicides, to evaluate their binding affinities. The Glide XP and YASARA docked complexes showed discrepancies in results, for scoring and ranking the binding affinities of fungicides. The docked complexes were further refined and rescored from their docked poses through 50 ns long MD simulations, and binding free energies (ΔGbind) calculations, using MM/GBSA analysis, revealed Oxathiapiprolin and Famoxadone as better fungicides among the selected one. However, Famoxadone had better interaction of the docked residues, with best protein ligand contacts, minimum RMSD (high accuracy of the docking pose) and RMSF (structural integrity and conformational flexibility of docking) at the specified docking site. The Famoxadone was found to be acceptable based on in silico toxicity and in vitro growth inhibition assessment. We conclude that the FOXG_04696, could be employed as a novel candidate protein, for structure-based design, and screening of target fungicides against the FOL pathogen.

/pdf/in-silico-prediction-characterization-molecular-docking-and-41mpbqw3ws.pdf

In silico Prediction, Characterization, Molecular Docking, and Dynamic Studies on Fungal SDRs as Novel Targets for Searching Potential Fungicides Against Fusarium Wilt in Tomato.

Streptococcus pneumoniae is a leading cause of some diseases such as pneumonia, sepsis, and meningitis mostly in children less than 5 years of age. Presently, two types of pneumococcal vaccine are ...

Vaccinomics approach for developing multi-epitope peptide pneumococcal vaccine.

c-Jun-NH2 terminal kinases (JNKs) come under a class of serine/threonine protein kinases and are encoded by three genes, namely JNK1, JNK2 and JNK3. Human JNK1 is a cytosolic kinase belonging to mitogen-activated protein kinase (MAPK) family, which plays a major role in intracrinal signal transduction cascade mechanism. Overexpressed human JNK1, a key kinase interacts with other kinases involved in the etiology of many cancers, such as skin cancer, liver cancer, breast cancer, brain tumors, leukemia, multiple myeloma and lymphoma. Thus, to unveil a novel human JNK1 antagonist, receptor-based pharmacophore modeling was performed with the available eighteen cocrystal structures of JNK1 in the protein data bank. Eighteen e-pharmacophores were generated from the 18 cocrystal structures. Four common e-pharmacophores were developed from the 18 e-pharmacophores, which were used as three-dimensional (3D) query for shape-based similarity screening against more than one million small molecules to generate a...

Inhibitor design against JNK1 through e-pharmacophore modeling docking and molecular dynamics simulations.

Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase which has attracted significant attention during recent years in drug design studies. The deregulation of GSK-3β increased the loss of hippocampal neurons by triggering apoptosis-mediating production of neurofibrillary tangles and alleviates memory deficits in Alzheimer’s disease (AD). Given its role in the formation of neurofibrillary tangles leading to AD, it has been a major therapeutic target for intervention in AD, hence was targeted in the present study. Twenty crystal structures were refined to generate pharmacophore models based on energy involvement in binding co-crystal ligands. Four common e-pharmacophore models were optimized from the 20 pharmacophore models. Shape-based screening of four e-pharmacophore models against nine established small molecule databases using Phase v3.9 had resulted in 1800 compounds having similar pharmacophore features. Rigid receptor docking (RRD) was performed for 1800 compounds and 20 co-crys...

E-pharmacophore-based virtual screening to identify GSK-3β inhibitors.

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 Schrodinger 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.

Exploring the Lead Compounds for Zika Virus NS2B-NS3 Protein: an e-Pharmacophore-Based Approach

196 Antiinflamatory activity of phenolic compounds extracted from Uruguayan propolis and grape Elena Alvareda*, Pablo Miranda, Victoria Espinosa, Helena Pardo, Sara Aguilera and Margot Paulino Zunini Centro de Bioinformática Estructural, DETEMA – Facultad de Química, UdelaR, Montevideo, Uruguay; Facultad de Química, Regional Norte; Centro Nanomat, Polo Tecnológico de Pando – Facultad de Química, UdelaR; Escuela de Medicina, Facultad de Ciencias Médicas – Universidad de Santiago de Chile (USACH); Departamento de Física, Universidad Católica del Norte – Chile *Email: alvareda@fq.edu.uy, Phone: (598) 473-20412 int 105

197 Combination of e-pharmacophore modeling, multiple docking strategies and molecular dynamic simulations to discover of novel antagonists of BACE1

Streptococcus pneumoniae (pneumococcus) remains an important cause of meningitis, bacteremia, acute otitis media, community acquired pneumonia associated with significant morbidity, and mortality world wide. Conjugated polysaccharide, glycoconjugated, and capsular polysaccharide based vaccines were existent for pneumococcal disease but are still specific and restricted to serotypes of S. pneumoniae. Proteome of eight serotypes of S. pneumoniae was retrieved and identified in common proteins (Munikumar et al., 2012). 18 membrane proteins were distinguished from 1657 common proteins of eight serotypes of S. pneumoniae. Implementing comparative genomic approach and subtractive genomic approach, three membrane proteins were predicted as essential for bacterial survival and non-homologous to human (Munikumar et al., 2012; Umamaheswari et al., 2011). ProPred server was used to propose four promiscuous T-cell epitopes from three membrane proteins and validated through published positive control, SYFPEITHI and im...

177 T-cell vaccine design for Streptococcus pneumoniae: an in silico approach

Infective endocarditis (IE) is a serious form of microbial infection of the endocardial surface, lining of the heart chambers and heart valves with a high mortality rate. Through comparative genomics, subtractive genomics, and metabolic pathway analysis, 18 common drug targets were identified (Priyadarshini et al., 2013). In the present study, β-Ketoacyl-acyl carrier protein synthase III (FabH), a common protein among eight selected pathogens of IE, was selected for the study. FabH catalyzes the initiation of fatty acid elongation by condensing malonyl-ACP with acetyl-CoA. FabH is an essential enzyme for bacterial viability, because of its pivotal roles in both initiation and regulation of the fatty acid biosynthesis. Experimentally determined tertiary structure of FabH of Streptococcus mitis (reference organism) was not reported yet. Therefore, molecular modeling of FabH in complex with 2-({[4-bromo-3-(diethylsulfamoyl) phenyl] carbonyl} amino) benzoic acid (B82) was constructed using Modeller9v10 (Figur...

176 Structure-based virtual screening towards identification of potential FabH inhibitors

Background: Alzheimer's disease (AD) is a neurodegenerative disorder in elderly persons aged above 65 years. The cleavage of amyloid precursor protein (APP) by -secretase generates peptide fragment A42, the main cause of memory and cognitive defects in AD. Therefore, elevated level of -secretase results in accumulation of insoluble form of A peptides (senile plaques) representing the protein as an attractive drug target of AD. Methods: Five recently reported -secretase antagonist (thiazolidinediones, rosiglitazone, pioglitazone, SC7 and tartaric acid) structural analogs were searched from ligand info database and prepared using LigPrep. The crystal structure of -secretase was optimized using Maestro v9.2 protein preparation wizard applying optimized potential for liquid simulations (OPLS)-2005 force field. Structure based virtual screening was performed for -secretase from prepared ligands using virtual screening workflow of Maestro v9.2 and was ranked based on XP Gscore. Results: Eight lead molecules were identified to have better binding affinity (lower XP Gscore) compared to five existing -secretase antagonists and appear to have good pharmacological properties. Binding orientations of the lead molecules were in well agreement with existing inhibitors. Lead1 showed lowest XP Gscore (-10.72 Kcal/mol). Molecular dynamics (MD) simulations of -secretase-lead1 complex was stable in all trajectories. Conclusion: Lead1 is proposed as potent inhibitor of -secretase and thus could be considered for rational drug design

/pdf/identification-of-potent-inhibitors-for-b-secretase-through-3k6m9yrk8c.pdf

Identification of potent inhibitors for β-secretase through structure based virtual screening and molecular dynamics simulations

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197 Combination of e-pharmacophore modeling, multiple docking strategies and molecular dynamic simulations to discover of novel antagonists of BACE1

177 T-cell vaccine design for Streptococcus pneumoniae: an in silico approach

176 Structure-based virtual screening towards identification of potential FabH inhibitors

Identification of potent inhibitors for β-secretase through structure based virtual screening and molecular dynamics simulations