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In silico repositioning of approved drugs against Schistosoma mansoni energy metabolism targets.

ABSTRACT: Schistosomiasis is a neglected parasitosis caused by Schistosoma spp. Praziquantel is used for the chemoprophylaxis and treatment of this disease. Although this monotherapy is effective, the risk of resistance and its low efficiency against immature worms compromises its effectiveness. Therefore, it is necessary to develop new schistosomicide drugs. However, the development of new drugs is a long and expensive process. The repositioning of approved drugs has been proposed as a quick, cheap, and effective alternative to solve this problem. This study employs chemogenomic analysis with use of bioinformatics tools to search, identify, and analyze data on approved drugs with the potential to inhibit Schistosoma mansoni energy metabolism enzymes. The TDR Targets Database, Gene DB, Protein, DrugBank, Therapeutic Targets Database (TTD), Promiscuous, and PubMed databases were used. Fifty-nine target proteins were identified, of which 18 had one or more approved drugs. The results identified 20 potential drugs for schistosomiasis treatment; all approved for use in humans.

SUBMITTER: Calixto NM

PROVIDER: S-EPMC6312253 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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In silico repositioning of approved drugs against Schistosoma mansoni energy metabolism targets.

Calixto Nicole Melo NM Dos Santos Daniela Braz DB Bezerra José Clecildo Barreto JCB Silva Lourival de Almeida LA

PloS one 20181231 12

Schistosomiasis is a neglected parasitosis caused by Schistosoma spp. Praziquantel is used for the chemoprophylaxis and treatment of this disease. Although this monotherapy is effective, the risk of resistance and its low efficiency against immature worms compromises its effectiveness. Therefore, it is necessary to develop new schistosomicide drugs. However, the development of new drugs is a long and expensive process. The repositioning of approved drugs has been proposed as a quick, cheap, and ...[more]

PMID: 30596650

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Project description:BackgroundThe chemotherapy of schistosomiasis currently depends on the use of a single drug, praziquantel. In order to develop novel chemotherapeutic agents we are investigating enzymes involved in the epigenetic modification of chromatin. Sirtuins are NAD+ dependent lysine deacetylases that are involved in a wide variety of cellular processes including histone deacetylation, and have been demonstrated to be therapeutic targets in various pathologies, including cancer.Methodology principal findingsIn order to determine whether Schistosoma mansoni sirtuins are potential therapeutic targets we first identified and characterized their protein sequences. Five sirtuins (SmSirt) are encoded in the S. mansoni genome and phylogenetic analysis showed that they are orthologues of mammalian Sirt1, Sirt2, Sirt5, Sirt6 and Sirt7. Both SmSirt1 and SmSirt7 have large insertion in the catalytic domain compared to their mammalian orthologues. SmSirt5 is the only mitochondrial sirtuin encoded in the parasite genome (orthologues of Sirt3 and Sirt4 are absent) and transcripts corresponding to at least five splicing isoforms were identified. All five sirtuins are expressed throughout the parasite life-cycle, but with distinct patterns of expression. Sirtuin inhibitors were used to treat both schistosomula and adult worms maintained in culture. Three inhibitors in particular, Sirtinol, Salermide and MS3 induced apoptosis and death of schistosomula, the separation of adult worm pairs, and a reduction in egg laying. Moreover, Salermide treatment led to a marked disruption of the morphology of ovaries and testes. Transcriptional knockdown of SmSirt1 by RNA interference in adult worms led to morphological changes in the ovaries characterized by a marked increase in mature oocytes, reiterating the effects of sirtuin inhibitors and suggesting that SmSirt1 is their principal target.Conclusion significanceOur data demonstrate the potential of schistosome sirtuins as therapeutic targets and validate screening for selective sirtuin inhibitors as a strategy for developing new drugs against schistosomiasis.

Project description:The membrane-anchored spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a pivotal role in directing the fusion of the virus particle mediated by the host cell receptor angiotensin-converting enzyme 2 (ACE-2). The fusion peptide region of the S protein S2 domain provides SARS-CoV-2 with the biological machinery needed for direct fusion to the host lipid membrane. In our present study, computer-aided drug design strategies were used for the identification of FDA-approved small molecules using the optimal structure of the S2 domain, which exhibits optimal interaction ratios, structural features, and energy variables, which were evaluated based on their performances in molecular docking, molecular dynamics simulations, molecular mechanics/generalized Born model and solvent accessibility binding free energy calculations of molecular dynamics trajectories, and statistical inferences. Among the 2,625 FDA-approved small molecules, chloramphenicol succinate, imipenem, and imidurea turned out to be the molecules that bound the best at the fusion peptide hydrophobic pocket. The principal interactions of the selected molecules suggest that the potential binding site at the fusion peptide region is centralized amid the Lys790, Thr791, Lys795, Asp808, and Gln872 residues.IMPORTANCE The present study provides the structural identification of the viable binding residues of the SARS-CoV-2 S2 fusion peptide region, which holds prime importance in the virus's host cell fusion and entry mechanism. The classical molecular mechanics simulations were set on values that mimic physiological standards for a good approximation of the dynamic behavior of selected drugs in biological systems. The drug molecules screened and analyzed here have relevant antiviral properties, which are reported here and which might hint toward their utilization in the coronavirus disease 2019 (COVID-19) pandemic owing to their attributes of binding to the fusion protein binding region shown in this study.

Project description:Schistosomiasis is an infectious disease infecting mammals as the definitive host and fresh water snails as the intermediate host. Understanding the molecular and biochemical relationship between the causative schistosome parasite and its hosts will be key to understanding and ultimately treating and/or eradicating the disease. There is increasing evidence that pathogens that have co-evolved with their hosts can manipulate their hosts' behaviour at various levels to augment an infection. Bacteria, for example, can induce beneficial chromatin remodelling of the host genome. We have previously shown in vitro that Biomphalaria glabrata embryonic cells co-cultured with schistosome miracidia display genes changing their nuclear location and becoming up-regulated. This also happens in vivo in live intact snails, where early exposure to miracidia also elicits non-random repositioning of genes. We reveal differences in the nuclear repositioning between the response of parasite susceptible snails as compared to resistant snails and with normal or live, attenuated parasites. Interestingly, the stress response gene heat shock protein (Hsp) 70 is only repositioned and then up-regulated in susceptible snails with the normal parasite. This movement and change in gene expression seems to be controlled by the parasite. Other differences in the behaviour of genes support the view that some genes are responding to tissue damage, for example the ferritin genes move and are up-regulated whether the snails are either susceptible or resistant and upon exposure to either normal or attenuated parasite. This is the first time host genome reorganisation has been seen in a parasitic host and only the second time for any pathogen. We believe that the parasite elicits a spatio-epigenetic reorganisation of the host genome to induce favourable gene expression for itself and this might represent a fundamental mechanism present in the human host infected with schistosome cercariae as well as in other host-pathogen relationships.

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In silico repositioning of approved drugs against Schistosoma mansoni energy metabolism targets.

Publications

In silico repositioning of approved drugs against Schistosoma mansoni energy metabolism targets.

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