The life-threatening infections caused by Leptospira serovars demand the need for designing anti-leptospirosis drugs. The present study encompasses exploring inhibitors against phosphoheptose isomerase (GmhA) of Leptospira, which is vital for lipopolysaccharide (LPS) biosynthesis and is identified as a common drug target through the subtractive genomic approach. GmhA model was built in Modeller 9v7. Structural refinement and energy minimization of the predicted model was carried out using Maestro 9.0. The refined model reliability was assessed through Procheck, ProSA, ProQ and Profile 3D. The substrate-based virtual high-throughput screening (VHTS) in Ligand.Info Meta-Database tool generated an in-house library of 354 substrate structural analogs. Furthermore, structure-based VHTS from the in-house library with different conformations of each ligand provided 14 novel competitive inhibitors. The model together with insight gained from the VHTS would be a promising starting point for developing anti-leptospirosis competitive inhibitors targeting LPS biosynthesis pathway.

The life-threatening infections caused by Leptospira serovars remain a global challenge since long time. Prevention of infection by controlling environmental factors being difficult to practice in developing countries, there is a need for designing potent anti-leptospirosis drugs. ATP-dependent MurD involved in biosynthesis of peptidoglycan was identified as common drug target among pathogenic Leptospira serovars through subtractive genomic approach. Peptidoglycan biosynthesis pathway being unique to bacteria and absent in host represents promising target for antimicrobial drug discovery. Thus, MurD 3D models were generated using crystal structures of 1EEH and 2JFF as templates in Modeller9v7. Structural refinement and energy minimization of the model was carried out in Maestro 9.0 applying OPLS-AA 2001 force field and was evaluated through Procheck, ProSA, PROQ, and Profile 3D. The active site residues were confirmed from the models in complex with substrate and inhibitor. Four published MurD inhibitors (two phosphinics, one sulfonamide, and one benzene 1,3-dicarbixylic acid derivative) were queried against more than one million entries of Ligand.Info Meta-Database to generate in-house library of 1,496 MurD inhibitor analogs. Our approach of virtual screening of the best-ranked compounds with pharmacokinetics property prediction has provided 17 novel MurD inhibitors for developing anti-leptospirosis drug targeting peptidoglycan biosynthesis pathway.

Yellow fever is among one of the most lethal viral diseases for which approved antiviral therapies were yet to be discovered. Herein, functional assignment of complete YFV proteome was done through support vector machine. Major envelope (E) protein that mediates entry of YFV into host cell was selected as a potent molecular target. Three dimensional structure of the molecular target was predicted using Modeller9v7. The model was optimized in Maestro9.0 applying OPLS AA force field and was evaluated using PROCHECK, ProSA, ProQ and Profile 3D. The BOG pocket residues Val48, Glu197, Thr200, Ile204, Thr265, Thr268 and Gly278 were located in YFV E protein using SiteMap2.3. More than one million compounds of Ligandinfo Meta database were explored using a computational virtual screening protocol targeting BOG pocket of the E protein. Finally, ten top ranked lead molecules with strong binding affinity to BOG pocket of YFV E protein were identified based on XP Gscore. Drug likeliness and comparative bioactivity analysis for these leads using QikProp3.2 had shown that these molecules would have the potential to act as better drug. Thus, the 10 lead molecules suggested in the present study would be of interest as promising starting point for designing antiviral compound against yellow fever.

Epitopes of Leptospira inducing CD4(+) T-cell responses by binding to human MHC molecules could critically contribute to the development of subunit vaccines for leptospirosis. Herein, we have identified unique vaccine peptides from outer membrane proteins (OMPs) common to four sequenced pathogenic Leptospira serovars through in silico reverse vaccinology technique. The OMPs were explored for probable antigens using jemboss and screened in ProPred subsequently to predict thirty HLA-DRB epitopes. The HLA-DRB epitopes were validated through published positive control (HA307-PKYVKQNTLKLAT-319), SYFPEITHI and immune epitope database (IEDB) to list twelve epitopes as putative subunit vaccine peptides from nine OMPs. Cation efflux system membrane protein (czcA) having four subunit vaccine peptides, was modeled in Modeller9v7 and evaluated through Procheck, ProSA and ProQ. The HLA-DRB alleles and czcA 3D interactions were studied using Hex 5.1. Further, the T-cell epitopes present in czcA were docked individually with HLA-DRB alleles. The docking result revealed that czcA and its epitopes were interacting well with HLA-DRB alleles, hence would certainly produce cell mediated immune response in host. Thus, czcA and its four subunit vaccine peptides would be ideal T-cell driven efficacious vaccine against leptospirosis.