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  • However most of these SBVS studies were

    2023-11-22

    However, most of these SBVS studies were focused on the target(s) for which crystal structures were available or have a similar template in PDB for comparative modeling. Besides, these were limited to SBVS only which relies on the rigid binding pocket, therefore, it may result in high false positives, particularly in the event of those receptor-ligand(s) interactions that bring significant conformational changes, as we noted in our example. So, in order to broaden the ambit of SBVS and making it more relevant, we propose a scheme to identify potential ‘hits’ against those targets as well whose structures, as of now, could only predict through Carmofur synthesis threading approaches (Fig. 1). Besides, we also present a ligand based binding site determination approach. In the present study, due to the uniqueness and functional annotation of a hypothetical unique protein of C. albicans (RefSeq: XP_722744.1; UniProtKB: Q5AMH1), we have selected nuclear Dam1 complex (or DASH complex) (especially subunit Ask1) as a potential antifungal target required for proper chromosome segregation and essential protein for viability, localized throughout the cell cycle. Candida albicans is an opportunistic human pathogen. Emergence of drug-resistant strains makes it necessary to develop new anti-candida drugs. C. albicans is a part of normal microbiota of humans and a fungal pathogen causes a range of infections especially candidiasis mostly in immunocompromised patients. During infection, candida proliferate as surface-adherent Carmofur synthesis of cells communities (biofilm existence). Candida cells in a biofilm are different from free-floating (planktonic) cells. Targeted subunit Ask1 plays an important role in chromosome segregation during mitosis. Its depletion in C. albicans causes a single nuclear mass with completely short spindle micro-tubules appearance and abnormally long astral microtubules that lead to cell arrest (Thakur and Sanyal, 2011). Besides, studied protein was also found unique to C. albicans after comparing with human and Saccharomyces cerevisiae proteomes (Tripathi et al., 2014; functionally known now, but covered then under the hypothetical category of unique proteins). Like C. albicans, only one microtubule binds to a kinetochore in S. cerevisiae. C. albicans has 3- to 5- kb long CENP-A-rich centromere sequences that are unique and different from each other on various chromosomes Thakur and Sanyal (2011). Reports also suggest that in C. albicans mainly four sub-proteins of evolutionary conserved outer kinetochore Dam1 complex are essential for viability and are localized at the kinetochore throughout the cell cycle. Prior studies conclude that the essentially of Dam1 complex, along with its exclusive presence across fungal species without a mammalian homolog, makes it an attractive novel drug target for the development of safe and more potent antifungal drug against candidiasis. Reports also suggest that Dam1 and Ask1, exhibited an exclusively short spindle phenotype with a single nuclear mass when depleted from C. albicans cells (Thakur and Sanyal, 2011). Studies suggest that abnormal growth of astral microtubules in the absence of Ask1 is due to the stabilization of microtubules by inhibiting their rate of depolymerization, this prevent cell cycle stage-specific spindle elongation and alignment, thus resulted in short and misaligned spindles. Prior experimental mutational studies suggest that Dam1 complex subunit Ask1 is essential for the survival of C. albicans as well as reported unique to it. Therefore, an Ask1 protein selected as a potential drug target for the development of potent and safer antifungal drug against candidiasis. The PubChem compounds database was used for hit screening. The present system may not only be instrumental in the enrichment of NCEs by identifying newer hits against a specific target molecule, but also provide an opportunity to know the light nature of ligands that may be useful in “one drug multiple targets” paradigm of drug discovery.