scholarly journals Virtual Screening on Marine Natural Products for Discovering TMPRSS2 Inhibitors

2021 ◽  
Vol 9 ◽  
Author(s):  
Mehdi Mahmudpour ◽  
Iraj Nabipour ◽  
Mohsen Keshavarz ◽  
Maryam Farrokhnia
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Marine Natural Products ◽  
Three Dimensional ◽  
Homology Model ◽  
Marine Natural Product ◽  
Dimensional Structure ◽  
Pharmacokinetic Properties ◽  
Transmembrane Serine Protease ◽  
Inhibitory Molecules

Although SARS-CoV-2 entry to cells strictly depends on angiotensin-converting enzyme 2 (ACE2), the virus also needs transmembrane serine protease 2 (TMPRSS2) for its spike protein priming. It has been shown that the entrance of SARS-CoV-2 through ACE2 can be blocked by cellular TMPRSS2 blockers. The main aim of this study was to find potential inhibitor(s) of TMPRSS2 through virtual screening against a homology model of TMPRSS2 using the library of marine natural products (MNPs). The homology modeling technique for generating a three-dimensional structure of TMPRSS2 was applied. Molecular docking, MM-GBSA and absorption, distribution, metabolism, excretion (ADME) evaluations were performed to investigate the inhibitory activity of marine natural products (MNPs) against TMPRSS2 and their pharmacokinetic properties. Camostat and nafamostat mesylate were used as the standard inhibitory molecules. Seven MNPs were able to inhibit TMPRSS2 better than the standard compounds. MNP 10 with CAS number 107503-09-3, called Watasenia β-D- Preluciferyl glucopyrasoiuronic acid, was found to be the best inhibitor of TMPRSS2 with acceptable pharmacokinetic properties. Herein, for the first time, a new marine natural product was introduced with potent inhibitory effects against TMPRSS2. MNP 10 exhibited favorable drug-like pharmacokinetic properties and it promises a novel TMPRSS2 blocker to combat SARS-CoV-2.

scholarly journals Discovery of Novel Inhibitors for Nek6 Protein through Homology Model Assisted Structure Based Virtual Screening and Molecular Docking Approaches

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
P. Srinivasan ◽  
P. Chella Perumal ◽  
A. Sudha
Keyword(s):  
Virtual Screening ◽  
Cell Cycle Progression ◽  
Three Dimensional ◽  
Homology Model ◽  
Mitotic Cell ◽  
Binding Pocket ◽  
Dynamics Simulation ◽  
Dimensional Structure ◽  
Amino Acid Residues ◽  
Relationship Of

Nek6 is a member of the NIMA (never in mitosis, gene A)-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602) were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.

scholarly journals CMNPD: a comprehensive marine natural products database towards facilitating drug discovery from the ocean

2020 ◽  
Vol 49 (D1) ◽  
pp. D509-D515
Author(s):  
Chuanyu Lyu ◽  
Tong Chen ◽  
Bo Qiang ◽  
Ningfeng Liu ◽  
Heyu Wang ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products ◽  
Terrestrial Plants ◽  
Activity Data ◽  
Related Data ◽  
Free Data ◽  
Pharmacokinetic Properties ◽  
Natural Products Discovery ◽  
User Friendly

Abstract Marine organisms are expected to be an important source of inspiration for drug discovery after terrestrial plants and microorganisms. Despite the remarkable progress in the field of marine natural products (MNPs) chemistry, there are only a few open access databases dedicated to MNPs research. To meet the growing demand for mining and sharing for MNPs-related data resources, we developed CMNPD, a comprehensive marine natural products database based on manually curated data. CMNPD currently contains more than 31 000 chemical entities with various physicochemical and pharmacokinetic properties, standardized biological activity data, systematic taxonomy and geographical distribution of source organisms, and detailed literature citations. It is an integrated platform for structure dereplication (assessment of novelty) of (marine) natural products, discovery of lead compounds, data mining of structure-activity relationships and investigation of chemical ecology. Access is available through a user-friendly web interface at https://www.cmnpd.org. We are committed to providing a free data sharing platform for not only professional MNPs researchers but also the broader scientific community to facilitate drug discovery from the ocean.

scholarly journals A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 384 ◽  
Author(s):  
Giuseppe Floresta ◽  
Emanuele Amata ◽  
Carla Barbaraci ◽  
Davide Gentile ◽  
Rita Turnaturi ◽  
...  
Keyword(s):  
Natural Products ◽  
Tumor Cell ◽  
Marine Natural Products ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Receptor Protein ◽  
Receptor Ligands ◽  
Tumor Cell Death ◽  
Targeting Therapy

Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ2) receptor. The σ2 receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, and the overexpression of σ2 receptors in several tumor cell lines has been well documented, with significantly higher levels in proliferating tumor cells compared to quiescent ones. This acknowledged feature has found practical application in the development of cancer cell tracers and for ligand-targeting therapy. In this context, the development of new ligands that target the σ2 receptors is beneficial for those diseases in which this protein is involved. In this paper, we conducted a search of new potential σ2 receptor ligands among a database of 1517 “small” marine natural products constructed by the union of the Seaweed Metabolite and the Chemical Entities of Biological Interest (ChEBI) Databases. The structures were passed through two filters that were constituted by our developed two-dimensional (2D) and three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) statistical models, and successively docked upon a σ2 receptor homology model that we built according to the FASTA sequence of the σ2/TMEM97 (SGMR2_HUMAN) receptor.

Address of the President Lord Blackett, O.M., C.H. at the Anniversary Meeting, 30 November 1970

1971 ◽  
Vol 177 (1046) ◽  
pp. 1-14
Keyword(s):  
Natural Products ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Biological Systems ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Theoretical Knowledge ◽  
Three Dimensional Structure ◽  
Subsequent Determination

Todd has made highly significant contributions to the chemistry of natural products, in particular in relation to compounds which play important roles in biological systems. His researches on vitamins B 1 , E and B 12 were most elegant and have had far-reaching implications, but none more so than his structural and synthetic studies in the nucleic acid field. Here he developed methods for the synthesis of the nucleosides and for their phosphorylation; his work on the way they are combined made possible the subsequent determination of the three-dimensional structure of the nucleic acids thereby providing the basis for much of the exciting activity in the nucleotide field today. Todd’s achievements arise out of a rare combination of theoretical knowledge and outstanding experimental skill, with the most judicious exploitation of modern techniques. His work and his quality as an investigator have been widely recognized by biologists as well as by organic chemists.

First identification of small-molecule inhibitors of Pontin by combining virtual screening and enzymatic assay

2012 ◽  
Vol 443 (2) ◽  
pp. 549-559 ◽  
Author(s):  
Judith Elkaim ◽  
Michel Castroviejo ◽  
Driss Bennani ◽  
Said Taouji ◽  
Nathalie Allain ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Small Molecule ◽  
Tumour Cell ◽  
Small Molecule Inhibitors ◽  
Colorimetric Assay ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Atp Binding Site ◽  
Set Up

The human protein Pontin, which belongs to the AAA+ (ATPases associated with various cellular activities) family, is overexpressed in several cancers and its silencing in vitro leads to tumour cell growth arrest and apoptosis, making it a good target for cancer therapy. In particular, high levels of expression were found in hepatic tumours for which the therapeutic arsenal is rather limited. The three-dimensional structure of Pontin has been resolved previously, revealing a hexameric assembly with one ADP molecule co-crystallized in each subunit. Using Vina, DrugScore and Xscore, structure-based virtual screening of 2200 commercial molecules was conducted into the ATP-binding site formed by a dimer of Pontin in order to prioritize the best candidates. Complementary to the in silico screening, a versatile and sensitive colorimetric assay was set up to measure the disruption of the ATPase activity of Pontin. This assay allowed the determination of inhibition curves for more than 20 top-scoring compounds, resulting in the identification of four ligands presenting an inhibition constant in the micromolar concentration range. Three of them inhibited tumour cell proliferation. The association of virtual screening and experimental assay thus proved successful for the discovery of the first small-molecule inhibitors of Pontin.

Address of the President Lord Blackett, O.M., C.H. at the Anniversary Meeting, 30 November 1970

1971 ◽  
Vol 321 (1544) ◽  
pp. 1-14
Keyword(s):  
Natural Products ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Biological Systems ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Theoretical Knowledge ◽  
Three Dimensional Structure ◽  
Subsequent Determination

The Copley Medal is awarded to Lord Todd, F. R. S. Todd has made highly significant contributions to the chemistry of natural products, in particular in relation to compounds which play important roles in biological systems. His researches on vitamins B 1 , E and B 12 were most elegant and have had far-reaching implications, but none more so than his structural and synthetic studies in the nucleic acid field. Here he developed methods for the synthesis of the nucleosides and for their phosphorylation; his work on the way they are combined made possible the subsequent determination of the three-dimensional structure of the nucleic acids thereby providing the basis for much of the exciting activity in the nucleotide field today. Todd’s achievements arise out of a rare combination of theoretical knowledge and outstanding experimental skill, with the most judicious exploitation of modern techniques. His work and his quality as an investigator have been widely recognized by biologists as well as by organic chemists.

scholarly journals A Review of the Secondary Metabolites From the Marine Sponges of the Genus Aaptos

2020 ◽  
Vol 15 (9) ◽  
pp. 1934578X2095143
Author(s):  
Qianqian He ◽  
Shuang Miao ◽  
Na Ni ◽  
Yuqing Man ◽  
Kaikai Gong
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Natural Product ◽  
Chemical Ecology ◽  
Marine Natural Products ◽  
Organic Molecules ◽  
Biological Activities ◽  
Marine Sponges ◽  
Marine Natural Product ◽  
Natural Product Research

Marine sponges, which belong to the phylum Porifera (Metazoa), are considered the single best source of marine natural products. Among them, members of the genus Aaptos are attractive targets for marine natural product research owing to their abundant biogenetic ability to produce aaptamine derivatives. Apart from aaptamine alkaloids, there are also reports of other compounds from Aaptos sponges. This work reviews the secondary metabolites isolated from Aaptos species from 1982 to 2020, with 46 citations referring to 62 compounds (47 for aaptamines and 15 for others). The emphasis is placed on the structure of the organic molecules, relevant biological activities, chemical ecology aspects, and biosynthesis studies, which are described in the classifications of aaptamines and other compounds in the order of the published year.

scholarly journals Structural model of a putrescine-cadaverine permease from Trypanosoma cruzi predicts residues vital for transport and ligand binding

2013 ◽  
Vol 452 (3) ◽  
pp. 423-432 ◽  
Author(s):  
Radika Soysa ◽  
Hanka Venselaar ◽  
Jacqueline Poston ◽  
Buddy Ullman ◽  
Marie-Pierre Hasne
Keyword(s):  
Trypanosoma Cruzi ◽  
Structural Model ◽  
Three Dimensional ◽  
Salt Bridge ◽  
Homology Model ◽  
Binding Pocket ◽  
Dimensional Structure ◽  
Helical Structures ◽  
Structural Determinants ◽  
Key Residues

The TcPOT1.1 gene from Trypanosoma cruzi encodes a high affinity putrescine-cadaverine transporter belonging to the APC (amino acid/polyamine/organocation) transporter superfamily. No experimental three-dimensional structure exists for any eukaryotic member of the APC family, and thus the structural determinants critical for function of these permeases are unknown. To elucidate the key residues involved in putrescine translocation and recognition by this APC family member, a homology model of TcPOT1.1 was constructed on the basis of the atomic co-ordinates of the Escherichia coli AdiC arginine/agmatine antiporter crystal structure. The TcPOT1.1 homology model consisted of 12 transmembrane helices with the first ten helices organized in two V-shaped antiparallel domains with discontinuities in the helical structures of transmembrane spans 1 and 6. The model suggests that Trp241 and a Glu247–Arg403 salt bridge participate in a gating system and that Asn245, Tyr148 and Tyr400 contribute to the putrescine-binding pocket. To test the validity of the model, 26 site-directed mutants were created and tested for their ability to transport putrescine and to localize to the parasite cell surface. These results support the robustness of the TcPOT1.1 homology model and reveal the importance of specific aromatic residues in the TcPOT1.1 putrescine-binding pocket.

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