Mizoribin as a inhibitor for leukocyte immunoglobulin receptor sub family A member3

The Leukocyte Immunoglobulin-like Receptors (LILRs) are a family of receptors that was broadly expressed on all leukocytes and have the ability to regulate their function. The increased levels of human LILRA3 in rheumatoid arthritis patients leads to stroke. In quest of designing novel inhibitors against LILRA3 an accurate homology model for the protein was based on crystal structures of 1GOX and 3P2T using Modeller 9V9. The use of multiple templates for structure prediction led us to propose a structure comprising all 439 amino acids of human LILRA3 for the first time. The best model was selected based on GA341 and DOPE score and further assessed through ProSA and PROCHECK. The validated structure was subjected to CASTp analysis ligand binding site determination. N-acetyl-glucosamine (NAG) that has binding affinity towards human LILRA3 was searched for structural analogs from Ligan.Info database. The structural analogs were docked with LILRA3 using Glide v5.7 to propose 17 potential inhibitors with better binding affinity compared to NAG (-7.13 Kcal/mol). Analysis of LILRA3-Lead1 (mizoribin) docking showed best XPGscore of -10.70 Kcal/mol with four hydrogen bonds with Thr425, Glu360, Ser433,Val419. The binding orientations of mizoribin correlated well with NAG binding orientations. Therefore, mizoribin would be encouraging for stroke treatment in rheumatoid arthritis patients

Functional annotation of human parvovirus b19 proteome and Molecular docking of VP1 protein with Teniposide

Parvovirus B19 is a common source of infection with a seroprevalence of 60-70% in the adult population. Human parvovirus causes several distinct clinical syndromes such as erythema, polyarthritis resembling rheumatoid arthritis, vasculitis, hydrops fetalis, myocarditis etc. Recent years have witnessed manifest increase in clinical knowledge of parvovirus B19-associated complications, diagnosis and treatment. Traditional immunosuppressive therapy being unsuccessful, anti-viral therapy might be worthy of consideration. Functional annotation of human parvoviral proteome may provide insights into role of viral proteome in its survival and pathogenic mechanisms. Availability of whole proteome in the open source aided functional annotation of protein using SVMprot. Protein functions common to both structural and non-structural proteins are metal -binding, lipid-binding, copper-binding, calcium-binding, zinc-binding, magnesium-binding, DNA-binding, RNA-binding, transmembrane and outer membrane group of proteins. VP1 protein of human parvovirus b19 being quiet important for its structural integrity and being non homologous to human proteome, was identified as an attractive molecular target for structure based drug discovery. 3D structure of target protein VP1protein is predicted based on VP2 protein from human parvovirus b19 using MODELLER9V6. The modeled structure is validated using PROCHECK. Binding sites were predicted in Discovery studio 2.0 and Teniposide was found to be best docked lead molecule among selected ligands those docked to the functionally important site 1 using LigandFit protocol. The docking complex shows teniposide forming strong hydrogen bond with serine 580 of modeled VP1 protein. The strong hydrogen bonding, hydrophobic interaction, Vander wall interaction marked by teniposide would affect the structural integrity of parvovirus B19 significantly. The detailed insight of structural, functional and interactive aspect of the protein is being studied would enable us delineate it as potential drug target. Also different docking poses generated through docking studies may be considered as a model for identifying drug candidate against parvovirus

Envelope protein as molecular target for YFV (Yellow fever virus) drug discovery

Yellow fever (YF), a mosquito-borne viral haemorrhagic fever, is one of the most lethal viral diseases. Despite the availability of vaccines, yellow fever virus (YFV) strikes an estimated 2, 00,000 persons world-wide each year and causes 30,000 deaths approximately. There are no approved antiviral therapies for the treatment of YFV disease in humans. YFV 17D strain RNA genome is of 10,862 nucleotides, which encodes three structural proteins (C, PrM, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Identification of different protein functions facilitates a mechanistic understanding of YFV infection and opens novel means for drug development. Functional assignment of complete YFV proteome was done through support Vector machine (SVM). Significant functions of YFV Envelope (E) protein are Transmembrane, Aptamer-binding protein, Coat protein, Zinc-binding, Manganese-binding and Metal-binding etc. The E protein being non homologous to human and important in receptor binding, hemagglutination of erythrocytes at acidic pH, induction of the protective immune response, and involvement in an intraendosomal acid-catalyzed fusion step necessary for infection was selected as a potent molecular target against YFV drug discovery. 3D structure of target protein E protein is predicted using MODELLER9V6 and validated through PROCHECK analysis. The Binding site tool of Discovery Studio 2.0 was used to find sites all over protein. Heparin was identified as an important ligand against the molecular target and was docked to the functionally important binding site using LigandFit protocol. The YFV E protein -Heparin docking complex associated with strong hydrogen bonding with SER 483, GLN 443 and ALA 441 residues. The strong docking interaction may impede the infection causes due to association of YFV E protein and Core membrane. Further, the predicted model can be used as reference towards designing candidate drugs against YFV

Para-(benzoyl)-phenylalanine as a potential inhibitor against leptospirosis

Leptospirosis is a zoonotic disease of global concern caused by Leptospira interrogans. Subtractive genomic approach, metabolic pathway analysis and multi strain genome comparisons of Leptospira interrogans serovars had proposed 88 common drug targets from 5,124 genes of serovar Copenhageni and 4,727 genes of serovar Lai. Three potential drug targets (lpxC, lpxD and lpxB) were identified from Lipid A biosynthesis process of lipopolysaccharide (LPS) biosynthesis pathway. Lipid A is one of the three components of LPS that contains multiple hydrophobic fatty acid chains which anchor the LPS into the bacterial membrane. Designing inhibitory drug molecules targeting Lipid A biosynthesis would dissolve the structural integrity of membrane structure leading to cell lysis and death of Leptospira. LpxC being the first enzyme among the three drug targets of Lipid A biosynthesis pathway; blocking the enzyme with suitable inhibitor would stop synthesizing substrates for lpxD and lpxB. Also, there is no alternative mechanism in Leptospira to replace the catalytic activity rendered by lpxC; hence, the drug target was selected herein for rational drug design. The lpxC tertiary structure was modeled incorporating inhibitor BB-78485 using Modeller9v8. The lpxC 3D structure reliability was assessed through various model validation techniques. Ligand based virtual screening was performed from one million entries of ligand.Info metadatabase. The leads were ranked using computational docking technique of Glidev5.5. Twelve leads with better binding affinity than BB-78485 (XPGscore -7.98 Kcal/mol) were proposed as potential inhibitors of lpxC. Para-(benzoyl)-phenylalanine, the best ranked inhibitor (XPGscore -10.34Kcal/mol), would be intriguing for rational drug design against leptospirosis

Structural insight to Streptococcus mitis thymidylate kinase: a potential common drug target of infective endocarditis

The incidence of infective endocarditis (IE) represents the fourth leading cause of life-threatening infectious disease with a yearly incidence of 15,000 to 20,000 new cases despite advances in antimicrobial therapy, development of better diagnostic and surgical techniques. The diverse group of causative microbes of IE is one of major obstacle towards development of effective antimicrobial drug. This has triggered exploration of common potential novel drug target from available whole genome sequences of predominant pathogens causing IE in SVIMS hospital through comparative subtractive genomic approach and metabolic pathway analysis. Streptococcus mitis is the most predominant IE pathogen in SVIMS hospital. Thymidylate kinase of Streptococcus mitis plays a vital role in pyrimidine metabolism in deoxyribonucleic acid (DNA) synthesis was identified as novel common drug target against IE. Computational tools were utilized further to gain insight on physico-chemical, structural and functional aspects of the protein for facilitating structure based drug design for discovery of novel drug molecule. Motifs and domains of thymidylate kinase were predicted. Secondary structural elements were predicted using NPS server and PROTEUS server. Three dimensional model of thymidylate kinase was constructed based on thymidylate kinase (2CCJ) of Staphylococcus aureus as template using Modeller9v7. DOPE score correlation, PROCHECK, ProSA and superpose results confirmed the predicted model is of good quality. The active site residues of thymidylate kinase were derived by incorporating natural substrate into predicted model from the template. Further, the active site was validated through multiple sequence alignment and CASTp analysis. The 3D model with predicted active site will aid in designing drug against organisms causing infective endocarditis