scholarly journals Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign

2020 ◽  
Vol 22 (1) ◽  
pp. 257
Author(s):  
Patricia Gomez-Gutierrez ◽  
Juan J. Perez
Keyword(s):  
Virtual Screening ◽  
Molecular Mechanisms ◽  
Partial Agonist ◽  
Drug Repurposing ◽  
Cytokine Storm ◽  
Bradykinin Receptors ◽  
Screening Process ◽  
Bradykinin Antagonists ◽  
Illness Progression

Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine storm observed in patients with severe Covid-19. In the scope of a drug repurposing campaign undertaken to identify bradykinin antagonists, raloxifene was identified as prospective compound in a virtual screening process. The pharmacodynamics profile of raloxifene towards bradykinin receptors is reported in the present work, showing a weak selective partial agonist profile at the B2 receptor. In view of this new profile, its possible use as a therapeutical agent for the treatment of severe Covid-19 is discussed.

scholarly journals Development of a Protocol for Virtual Screening of PPARγ Weak Partial Agonists and Their Metabolites: Case Study on Naturally-derived Oleanane Triterpenoids

2021 ◽  
Vol 25 (2) ◽  
pp. 117-132
Author(s):  
Merilin Al Sharif ◽  
◽  
Petko Alov ◽  
Vessela Vitcheva ◽  
Antonia Diukendjieva ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Molecular Mechanisms ◽  
Partial Agonist ◽  
Mechanistic Explanation ◽  
Binding Mode ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Partial Agonists ◽  
Docking Protocol ◽  
Agonistic Activity

Triterpenoids are well known metabolic syndrome (MetS) modulators. One of the suggested molecular mechanisms of action involves peroxisome proliferator-activated receptor gamma (PPARγ) activation. In this study we aimed to: (i) develop a virtual screening (VS) protocol for PPARγ weak partial agonists, (ii) predict potential metabolic transformations of naturally-derived triterpenoids, and (iii) perform VS of the triterpenoids and their metabolites. The NIH PubMed system was searched for publications about naturally-derived oleanane triterpenoids which are agonists or up-regulators of PPARγ. Structure- and ligand-based methods were combined in the development of the VS protocol. Metabolites were predicted using Meteor Nexus expert system (Lhasa Limited). Two in-house virtual libraries of PPARγ weak partial agonists and naturally-derived triterpenoids with their predicted metabolites were compiled. The pharmacophore-based docking protocol was applied for VS of the collected triterpenoids. Most of the docking poses reproduced the binding mode of caulophyllogenin (a weak partial agonist) in a complex with PPARγ (PDB ID 5F9B). Our results contribute to the mechanistic explanation of the effects of triterpenoids suggesting possible weak partial agonistic activity toward PPARγ. This research can direct further studies on triterpenoids’ role in MetS modulation. The developed protocol can be applied for VS of any PPARγ weak partial agonists.

Does the Oxazolidinone Derivatives Constitute a Functional Approach for Cancer Therapy?

2020 ◽  
Vol 7 (2) ◽  
pp. 95-106
Author(s):  
Eduardo Augusto Vasconcelos de Freitas Ramalho ◽  
Marina Galdino da Rocha Pitta ◽  
Hernando de Barros Siqueira Neto ◽  
Ivan da Rocha Pitta
Keyword(s):  
Cell Lines ◽  
Antitumor Agents ◽  
Partial Agonist ◽  
Drug Repurposing ◽  
Antitumor Agent ◽  
Short Review ◽  
Sphingolipid Metabolism ◽  
Solid Cancer ◽  
Ppar Γ ◽  
Anti Cancer

In the last four decades, the emphasis was laid on the research of small organic molecules with potential anti-cancer activity. Linezolid was the first oxazolidinone derivative approved by FDA for MRSA treatment. Despite its major role in antimicrobial activity, these molecules display other properties, also serving as an antitumor agent. The importance of drug repurposing could be highlighted by the use of Oxazolidinone derivatives in pre-clinical studies, which are able to act through different pathways, such as partial agonist of transcription factor PPAR-γ, an inhibitor of key enzymes related to hormone-dependent disorders and even on sphingolipid metabolism as well. The purpose of this short review is to discuss the application of oxazolidinone derivatives as an antitumor agent by highlighting the most promising molecules studied by many research groups worldwide. Main biological activity against several tumor cell lines, including hematopoietic and solid cancer cell lines have been discussed. In addition, this study intends to report how different types of oxazolidinone derivatives can act as antitumor agents describing their distinct mechanisms of action based on their targets.

scholarly journals Promising drug repurposing approach targeted for cytokine storm implicated in SARS-CoV-2 complications

2021 ◽  
pp. 1-15
Author(s):  
May Ahmed Shawki ◽  
Noha Salah Elsayed ◽  
Eman M. Mantawy ◽  
Riham S. Said
Keyword(s):  
Drug Repurposing ◽  
Cytokine Storm

scholarly journals Haste makes waste: A critical review of docking‐based virtual screening in drug repurposing for SARS‐CoV‐2 main protease (M‐pro) inhibition

2021 ◽  
Author(s):  
Guillem Macip ◽  
Pol Garcia‐Segura ◽  
Júlia Mestres‐Truyol ◽  
Bryan Saldivar‐Espinoza ◽  
María José Ojeda‐Montes ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Critical Review ◽  
Drug Repurposing ◽  
Main Protease

scholarly journals A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0

2020 ◽  
Vol 21 (14) ◽  
pp. 5152 ◽  
Author(s):  
Silvia Gervasoni ◽  
Giulio Vistoli ◽  
Carmine Talarico ◽  
Candida Manelfi ◽  
Andrea R. Beccari ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Protein Targets ◽  
In Silico Studies ◽  
Allosteric Sites ◽  
Binding Pockets ◽  
Novel Strategy ◽  
Better Than ◽  
Comprehensive Mapping

(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico studies; (2) Methods: Along with a careful literature search on SARS-CoV-2 protein targets, the study presents a novel strategy for pocket mapping based on the combination of pocket (as performed by the well-known FPocket tool) and docking searches (as performed by PLANTS or AutoDock/Vina engines); such an approach is implemented by the Pockets 2.0 plug-in for the VEGA ZZ suite of programs; (3) Results: The literature analysis allowed the identification of 16 promising binding cavities within the SARS-CoV-2 proteins and the here proposed approach was able to recognize them showing performances clearly better than those reached by the sole pocket detection; and (4) Conclusions: Even though the presented strategy should require more extended validations, this proved successful in precisely characterizing a set of SARS-CoV-2 druggable binding pockets including both orthosteric and allosteric sites, which are clearly amenable for virtual screening campaigns and drug repurposing studies. All results generated by the study and the Pockets 2.0 plug-in are available for download.

scholarly journals Multiple Virtual Screening Strategies for the Discovery of Novel Compounds Active Against Dengue Virus: A Hit Identification Study

2019 ◽  
Vol 88 (1) ◽  
pp. 2 ◽  
Author(s):  
Kowit Hengphasatporn ◽  
Arthur Garon ◽  
Peter Wolschann ◽  
Thierry Langer ◽  
Shigeta Yasuteru ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Dengue Infection ◽  
Md Simulations ◽  
Viral Envelope ◽  
Screening Process ◽  
Active Inhibitor ◽  
Effective Prevention ◽  
E Protein ◽  
Drug Databases ◽  
Promising Target

Dengue infection is caused by a mosquito-borne virus, particularly in children, which may even cause death. No effective prevention or therapeutic agents to cure this disease are available up to now. The dengue viral envelope (E) protein was discovered to be a promising target for inhibition in several steps of viral infection. Structure-based virtual screening has become an important technique to identify first hits in a drug screening process, as it is possible to reduce the number of compounds to be assayed, allowing to save resources. In the present study, pharmacophore models were generated using the common hits approach (CHA), starting from trajectories obtained from molecular dynamics (MD) simulations of the E protein complexed with the active inhibitor, flavanone (FN5Y). Subsequently, compounds presented in various drug databases were screened using the LigandScout 4.2 program. The obtained hits were analyzed in more detail by molecular docking, followed by extensive MD simulations of the complexes. The highest-ranked compound from this procedure was then synthesized and tested on its inhibitory efficiency by experimental assays.

scholarly journals Identification of Potential Dipeptidyl Peptidase (DPP)-IV Inhibitors among Moringa oleifera Phytochemicals by Virtual Screening, Molecular Docking Analysis, ADME/T-Based Prediction, and In Vitro Analyses

Molecules ◽  
2020 ◽  
Vol 25 (1) ◽  
pp. 189 ◽  
Author(s):  
Yang Yang ◽  
Chong-Yin Shi ◽  
Jing Xie ◽  
Jia-He Dai ◽  
Shui-Lian He ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Moringa Oleifera ◽  
Molecular Mechanisms ◽  
Dipeptidyl Peptidase ◽  
In Vivo Evaluation ◽  
Docking Analysis ◽  
Dpp Iv ◽  
Molecular Docking Analysis

Moringa oleifera Lam. (MO) is called the “Miracle Tree” because of its extensive pharmacological activity. In addition to being an important food, it has also been used for a long time in traditional medicine in Asia for the treatment of chronic diseases such as diabetes and obesity. In this study, by constructing a library of MO phytochemical structures and using Discovery Studio software, compounds were subjected to virtual screening and molecular docking experiments related to their inhibition of dipeptidyl peptidase (DPP-IV), an important target for the treatment of type 2 diabetes. After the four-step screening process, involving screening for drug-like compounds, predicting the absorption, distribution, metabolism, excretion, and toxicity (ADME/T) of pharmacokinetic properties, LibDock heatmap matching analysis, and CDOCKER molecular docking analysis, three MO components that were candidate DPP-IV inhibitors were identified and their docking modes were analyzed. In vitro activity verification showed that all three MO components had certain DPP-IV inhibitory activities, of which O-Ethyl-4-[(α-l-rhamnosyloxy)-benzyl] carbamate (compound 1) had the highest activity (half-maximal inhibitory concentration [IC50] = 798 nM). This study provides a reference for exploring the molecular mechanisms underlying the anti-diabetic activity of MO. The obtained DPP-IV inhibitors could be used for structural optimization and in-depth in vivo evaluation.

Sign in / Sign up

Export Citation Format

Share Document