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Multiple sequence alignment of the protein sequence SmCL1 and other six templates selected. The boxes indicate the conserved cysteine, histidine and asparagine catalytic regions. The catalytic residues forming the triad: Cys25, His161 and Asn182 are highlighted dark green. Glutamine (Gln19) involved in the formation of oxyanion hole is highlighted purple. The residues highlighted orange are cysteine residues forming disulphide bonds. The residues highlighted with blue, yellow, pink and light green correspond to S2, S1, S1’ and S3 pockets, respectively. RGD binding motif of SmCL1 is highlighted in black.
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Schistosomiasis is a major endemic disease known for excessive mortality and morbidity in developing countries. Because praziquantel is the only drug available for its treatment, the risk of drug resistance emphasizes the need to discover new drugs for this disease. Cathepsin SmCL1 is the critical target for drug design due to its essential role in...
Citations
... Oleh karena itu, semakin rendah nilai G (semakin besar nilai negatif), semakin tinggi energi ikat antara ligan dan protein target [20]. Selain itu, Zafar et al. [21] menyatakan bahwa terdapat hubungan linier antara nilai konstanta penghambatan (Ki) dengan nilai energi ikatan. Dengan demikian, nilai energi ikatan dapat digunakan untuk memprediksi kemampuan suatu senyawa dalam menghambat protein. ...
Hipertensi merupakan salah satu masalah kesehatan terbesar yang menjadi penyebab utama kematian di seluruh dunia. Angiotensin converting enzyme inhibitor (ACE-I) sebagai obat antihipertensi yang umum diketahui memiliki efek samping yang sering dikeluhkan. Penelitian ini bertujuan untuk mengidentifikasi senyawa potensial yang berasal dari pala (Myristica fragrans) sebagai antihipertensi dengan menggunakan studi penambatan molekular. Dua puluh tiga senyawa pala bersama dengan captopril digunakan dalam penelitian ini melalui pencarian literatur dan penyaringan daring. Senyawa dan obat pembanding diunduh melalui PubChem sementara reseptor target pada pada RCSB. Swiss ADME, ProTox-II, dan admetLab digunakan untuk mengevaluasi senyawa mirip obat dan memprediksi toksisitas senyawa. Senyawa dan captopril dilakukan penambatan molekular pada reseptor target ACE menggunakan Autodock tools 1.5.6 dan Autodock Vina serta visualisasi interaksi molekul dengan aplikasi Discovery Studio v16. Hasil penelitian menunjukkan seluruh senyawa memenuhi kriteria sebagai obat dan memiliki afinitas terhadap ACE. Catechin, beta-caryophyllene, dan alpha-bergamoten tidak toksik dan menunjukkan interaksi molekul yang kuat pada ACE dibanding dengan captopril dan senyawa lain dengan energi ikatan masing-masing -8,2, -7,3, -7,2 kkal/mol. Catechin, beta-caryophyllene, dan alpha-bergamoten berpotensi untuk dikembangkan sebagai ACE-I. Penelitian in vitro dan in vivo lebih lanjut diperlukan agar dapat dilakukan uji klinis.
... Thus, the value of binding energy can be used to predict the ability of a compound to inhibit proteins. [22] Jin et al. reported that the threshold of binding energy is ≤ -5.0 kcal/mol, so values less than -5.0 kcal/mol are considered to have strong binding effect with the key proteins. [23] A molecular docking study conducted by Hussain et al. showed that the binding sites of TMPRSS2 were amino acid residues of Gln276, Arg413, Glu299, and Thr387. ...
COVID-19 pandemic caused by SARS-CoV-2 is a challenge for researchers to find effective drugs for this disease. Previous research had identified the role of Mpro, TMPRSS2, RdRp, and ACE2 which were useful as promising drug targets to inhibit SARS-CoV-2. This study aims to identify the potential compounds derived from Ginkgo biloba as potential SARS-CoV-2 inhibitors using a molecular docking study. A total of twenty-one compounds of Ginkgo biloba and comparative drugs were used in this study. The materials were downloaded from rcsb for protein targets and pubchem for comparative drugs and compounds. In this study, Lipinski rule of five using Swiss ADME web tool was used. Moreover, toxicity analysis using admetSAR 2.0 online test also used to predict toxicological profile of compounds. Dockings were carried out on Mpro, TMPRSS2, RdRp, and ACE2 protein targets by AutodockTools 1.5.6 and Autodock Vina. The visualization of molecular interaction was carried out by Discovery Studio v16. Nine compounds met the criteria as drug-like components and were safe. Docking results showed that ginkgolide-C and bilobetin showed strong molecular interactions to all protein targets compared to the comparative drugs and other compounds. In RdRp, ginkgolide-C showed the highest binding energy with -12.7 kcal/mol. Moreover, in TMPRSS2, ACE2 and Mpro, bilobetin also showed the highest binding energy with -12.7, -9.7 and -10 kcal/mol, respectively. Ginkgolide-C and bilobetin have the potential to be developed as SARS-CoV-2 inhibitors. Therefore, in vitro and in vivo investigations are needed to bring these compounds to the clinical setting.
... As the genome of S. mansoni, S. japonicum and S. haematobium are known target-based studies are possible. Several proteins were identified as PZQ targets such as tyrosine kinase, tubulin, purine nucleoside phosphorylase, 3-ocoacetyl-ACP reductase, histone deacetylase (all cited in Ferreira et al. [25]) as well as cathepsin SmCL1 [26], glutathione S-reductase, thioredoxin glutathione reductase and arginase [27], which allowed several drug design studies using bioinformatics approaches. ...
Praziquantel (PZQ) is the first line drug for the treatment of human Schistosoma spp. worm infections. However, it suffers from low activity towards immature stages of the worm, and its prolonged use induces resistance/tolerance. During the last 40 years, 263 PZQ analogues have been synthesized and tested against Schistosoma spp. worms, but less than 10% of them showed significant activity. Here, we propose a rationalization of the chemical space of the PZQ derivatives by a ligand-based approach. First, we constructed an in-house database with all PZQ derivatives available in the literature. This analysis shows a high heterogeneity in the data. Fortunately, all studies include PZQ as a reference, permitting the classification of compounds into three classes according to their activities. Models involving ligand-based pharmacophore and logistic regression were performed. Five physicochemical parameters were identified as the best to explain the biological activity. In the end, we proposed new PZQ derivatives with modifications at positions 1 and 7, we analysed them with our models, and we observed that they can be more active than the previously synthesized derivatives. The main goal of this work was to conduct the most valuable meta-pharmacometrics/pharmacoinformatics analysis with all Praziquantel medicinal chemistry data available in the literature.
... Hence, for reliable and safer drug therapy, discovery and optimisation of non-peptide inhibitors/drugs is important (Mugumbate et al., 2013). Moreover, in a recent in silico identification of the drug molecules for Cathepsin L (SmCL1) of the organism Schistosoma mansoni responsible for the disease schistosomiasis, it was revealed that non-peptide molecules could be better drug molecules as compared to peptide molecules (Zafar et al., 2015). Table 2 briefly describes a list of popular software tools based on FCA. ...
Owing to the rapid advancement in high-throughput technologies, such as microarrays and next generation sequencing, the volume of biological data is increasing exponentially. The current challenge in computational biology and bioinformatics research is how to analyse these huge raw biological datasets to extract meaningful biological knowledge. Formal concept analysis is a method based on lattice theory and widely used for data analysis, knowledge representation, knowledge discovery and knowledge management across several domains. This paper reviews the applications of formal concept analysis for knowledge discovery from biological data, including gene expression discretisation, gene co-expression mining, gene expression clustering, finding genes in gene regulatory networks, enzyme/protein classifications, binding site classifications, and domain-domain interaction. It also presents a list of FCA-based software tools applied to the biological domain, and covers the challenges and future directions in this field.
... Hence, for reliable and safer drug therapy, discovery and optimisation of non-peptide inhibitors/drugs is necessary [28]. Moreover, in a recent in silico identifications of the drug molecules for Cathepsin L (SmCL1) of the organism, Schistosoma mansoni responsible for the disease schistosomiasis, it was revealed that the non-peptide molecules could be better drug molecules as compared to peptide drugs molecules [30]. The list of popularly used software tool based on FCA is shown in Table 1. ...
Due to rapid advancement in high-throughput techniques, such as microarrays
and next generation sequencing technologies, biological data are increasing
exponentially. The current challenge in computational biology and
bioinformatics research is how to analyze these huge raw biological data to
extract biologically meaningful knowledge. This review paper presents the
applications of formal concept analysis for the analysis and knowledge
discovery from biological data, including gene expression discretization, gene
co-expression mining, gene expression clustering, finding genes in gene
regulatory networks, enzyme/protein classifications, binding site
classifications, and so on. It also presents a list of FCA-based software tools
applied in biological domain and covers the challenges faced so far.
Schistosomiasis, a severe parasitic disease, is primarily caused by Schistosoma mansoni, Schistosoma japonicum, or Schistosoma haematobium. Currently, praziquantel is the only recommended drug for human schistosome infection. However, the lack of efficacy of praziquantel against juvenile worms and concerns about the emergence of drug resistance are driving forces behind the research for an alternative medication. Schistosomes are obligatory parasites that survive on nutrients obtained from their host. The ability of nutrient uptake depends on their physiological structure. In short, the formation and maintenance of the structure and nutrient supply are mutually reinforcing and interdependent. In this review, we focus on the structural features of the tegument, esophagus, and intestine of schistosomes and their roles in nutrient acquisition. Moreover, we introduce the significance and modes of glucose, lipids, proteins, and amino acids intake in schistosomes. We linked the schistosome structure and nutrient supply, introduced the currently emerging targets, and analyzed the current bottlenecks in the research and development of drugs and vaccines, in the hope of providing new strategies for the prevention and control of schistosomiasis.
Schistosomiasis is a chronic neglected tropical disease, highlighted by the presence of Schistosoma worms, which presents in advanced cases in approximately 80 countries, affecting almost 300 million people. The treatment is based on only one drug, praziquantel, a drug discovered in the 1970s that shows moderate efficacy against the adult parasite, but low efficacy against the larval stages of the parasite. Therefore, the use of only one drug has brought concerns and losses on drug-resistance cases, necessitating the development of new effective chemotherapeutic agents against Schistosoma species. One of the strategies that have been implemented in drug development is the computer-aided drug design (CADD), investigating the structural characteristics of the compounds and targets in order to understand their actions and biological activities through 3D virtual manipulation, as the QSAR applied to ligands and molecular docking applied to a respective biological target. These studies help to extract information and characteristics relevant to the activity, as well as to predict potential applications and activity. Therefore, this chapter will present the main validated biological targets of the genus Schistosoma, as thioredoxin glutathione reductase (TGR), histone deacetylases (HDAC 1, HDAC 8), dihydroorotate dehydrogenase, sirtuin protein and cathepsin L1, as well as reports of CADD in literature applied to the development of drugs against schistosomiasis, providing compounds with high pharmacological potential and high specificity.
This study describes the isolation and purification of a phytocystatin from seeds of Brassica juncea (B.juncea), (cultivar RoAgro 5444), an important oilseed crop with pervasive agricultural and economic ramifications. The protein was purified by gel filtration chromatography with 24.3% yield and 204 fold purification and visualised by 2D gel electrophoresis. The 18.1kDa mustard cystatin was highly specific for cysteine proteinases. The plant cystatin inhibited cathepsin B, confirming its role in conferring pest resistance. The inhibitor was highly stable over a pH range of 3-10 and retained significant inhibitory potential till 70ºC. The stoichiometry of its interaction with papain, determined by Isothermal Calorimetry suggests a 1:1 complex. Secondary structural elements calculated by far UV circular dichroism (CD) spectroscopy show 18.8% α helical and 21% β sheet structure. The protein was a non-competitive inhibitor of thiol proteinases. The stoke’s radius and frictional co-efficient were used to describe the shape and size of the protein.Homology modelling and docking studies proposed a prototype illustrating the Brassica phytocystatin mediated papain inhibition. Molecular dynamics (MD) study revealed prominent stability of papain-phytocystatin complex during 100 nanoseconds (ns) long simulation. Detailed results identify the mustard cystatin as an important member of the phytocystatin family.
