Robin, T. B. | bioRxiv Science

bioRxiv2022

In Silico Proteomics Approach Towards the Identification of Potential Novel Drug Targets Against Cryptococcus gattii

Cryptococcosis is a condition caused by inhaling Cryptococcus gattii, the tiny fungus from the environment. It is thought that the pathogen C. gattii is clinically more virulent than C. neoformans and could be a vicious agent in coming decades. It can enter the hosts brain and harm human peripheral blood mononuclear cells DNA (PBMCs). It is vital to investigate potential alternative medications to treat this disease since global antifungal resistance preventing Cryptococci infections is on the rise, leading to treatment failure. In order to find effective novel drug targets for C. gattii, a comprehensive novel approach has been used in conjunction with in silico analysis. Among 6561 proteins of C. gattii we have found three druggable proteins (XP 003194316.1, XP 003197297.1, XP 003197520.1) after completing a series of steps including exclusion of paralogs, human homologs, non-essential and human microbiome homologs proteins. These three proteins are involved in pathogen specific pathways, and can be targeted for drugs to eliminate the pathogen from the host. The subcellular locations and their interactions with a high number of proteins also demonstrate their eligibility as potential drug targets. We have approached their secondary, tertiary model and docked them with 21 potential antifungal plant metabolites. From the molecular docking analysis, we found Amentoflavone, Baicalin, Rutin and Viniferin to be the most effective drugs to stop such proteins because of their increased binding affinity. Correspondingly, the drugs showed proper ADME properties and also analyzed to be safe (Figure 9, Table 6). Moreover, these potential drugs can successfully be used in the treatment of Cryptococcosis caused by the fungus Cryptococcus gattii. In vivo trail is highly recommended for further prospection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/502060v1_fig9.gif" ALT="Figure 9"> View larger version (29K): org.highwire.dtl.DTLVardef@1e1d79borg.highwire.dtl.DTLVardef@122e30org.highwire.dtl.DTLVardef@19667eaorg.highwire.dtl.DTLVardef@18063a6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 9:C_FLOATNO SwissADME properties of top metabolites C_FIG O_TBL View this table: org.highwire.dtl.DTLVardef@e46d5org.highwire.dtl.DTLVardef@14c66b3org.highwire.dtl.DTLVardef@ea8b0eorg.highwire.dtl.DTLVardef@4f4bc8org.highwire.dtl.DTLVardef@1f85c8e_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 06:C_FLOATNO O_TABLECAPTIONTop metabolites with toxicity prediction C_TABLECAPTION C_TBL

bioinformatics↗

bioRxiv2022

Subtractive proteomics analysis to uncover the potent drug targets for distinctive drug design of Candida auris

Candida auris is a serious health concern of current world that possess serious global health threat and is emerging at a high rate. Available antifungal drugs are failing to combat this pathogen as they are growing resistance toward those drugs and some strains have already showed resistant to all three available antifungal drugs in the market. Finding alternative treatments is a must, therefore, to save lives from this foe. To make the way easier for developing new treatments, we have made some insilico analysis of this pathogen to identify suitable targets for designing drugs and also suggested some potential metabolites to test in vivo condition after some computational analysis. After the subtraction of duplicate, non-essential, human homologs, non-metabolic, human microbiome similar and druggable proteins we ended up with three proteins (XP_028890156.1, XP_028891672.1 and XP_028891858.1) from a total of 5441 C. auris proteins. Blocking those proteins will result in the destruction of the pathogen while the host will remain safe from unintentional blocking. Their subcellular locations and interaction with high number of proteins also indicate their suitability as drug target candidates. After analyzing in silico docking of 29 potential antifungal from plant origin with those three proteins we selected Caledonixanthone E, Viniferin, Glaucine, Jatrorrhizine as the most potent weapon to block those proteins as they showed higher binding affinity. Furthermore, they were predicted to be safe and also showed proper ADME properties (Figure 1). O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/487516v1_fig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@5ac4bcorg.highwire.dtl.DTLVardef@12a4b3eorg.highwire.dtl.DTLVardef@1b1d825org.highwire.dtl.DTLVardef@e581b3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Schematic pipeline of the process C_FIG

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