Insight into the Mechanism of 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibition by the Androsterone Derivative RM-532-105

2020 ◽  
Vol 16 (3) ◽  
pp. 243-250
Author(s):  
Preyesh Stephen ◽  
Jenny Roy ◽  
René Maltais ◽  
Donald Poirier
Keyword(s):  
Homology Model ◽  
Hydroxysteroid Dehydrogenase ◽  
Enzymatic Assays ◽  
Enzyme Binding ◽  
Structure Activity ◽  
Potential Binding ◽  
Competitive Action ◽  
Type 3 ◽  
Insight Into ◽  
Selection Of

Background: The last step in the production of androgen testosterone from 4-androstene- 3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known. Objective: To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH, as well as inhibitor RM-532-105. Methods: Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand, a homology model was prepared followed by molecular docking, and enzymatic assay experiments were performed. Results: Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione. Conclusion: These results allow the selection of one inhibitor orientation in the enzyme binding site, from the two possibilities predicted by the docking experiments, and appear to be in agreement with previous structure-activity relationships.

scholarly journals Substituted Aryl Benzylamines as Potent and Selective Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 3

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7166
Author(s):  
Nigel Vicker ◽  
Helen V. Bailey ◽  
Joanna M. Day ◽  
Mary F. Mahon ◽  
Andrew Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Therapeutics ◽  
Homology Model ◽  
Hydroxysteroid Dehydrogenase ◽  
Docking Studies ◽  
Cancer Cell Growth ◽  
In Silico Docking ◽  
X Ray Crystallography ◽  
Ic50 Values ◽  
Type 3

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC50 17β-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC50 values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC50 of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC50 of 74 nM. Racemic C-allyl derivative 26 (IC50 of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC50 of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth.

Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

2020 ◽  
Author(s):  
Luke Adams ◽  
Lorna E. Wilkinson-White ◽  
Menachem J. Gunzburg ◽  
Stephen J. Headey ◽  
Martin J. Scanlon ◽  
...  
Keyword(s):  
Binding Site ◽  
Systematic Approach ◽  
Structural Information ◽  
Peptide Binding ◽  
Chemical Diversity ◽  
Chemical Probes ◽  
Protein Targets ◽  
Structure Activity ◽  
Peptide Binding Site ◽  
Selection Of

The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.<br>

An Insight into Oligopeptide Transporter 3 (OPT3) family proteins

2020 ◽  
Vol 27 ◽  
Author(s):  
Fırat Kurt
Keyword(s):  
Stress Responses ◽  
Chelating Agent ◽  
Biological Processes ◽  
Biotic And Abiotic Stress ◽  
Oligopeptide Transporter ◽  
Binding Residues ◽  
Fe Homeostasis ◽  
Proteins Interactions ◽  
Insight Into ◽  
Selection Of

: Oligopeptide transporter 3 (OPT3) proteins are one of the subsets of OPT clade, yet little is known about these transporters. Therefore, homolog OPT3 proteins in several plant species were investigated and characterized using bioinformatical tools. Motif and co-expression analyses showed that OPT3 proteins may be involved in both biotic and abiotic stress responses as well as growth and developmental processes. AtOPT3 usually seemed to take part in Fe homeostasis whereas ZmOPT3 putatively interacted with proteins involved in various biological processes from plant defense system to stress responses. Glutathione (GSH), as a putative alternative chelating agent, was used in the AtOPT3 and ZmOPT3 docking analyses to identify their putative binding residues. The information given in this study will contribute to the understanding of OPT3 proteins’ interactions in various pathways and to the selection of potential ligands for OPT3s.

scholarly journals Effects of Glucosinolate-Derived Isothiocyanates on Fungi: A Comprehensive Review on Direct Effects, Mechanisms, Structure-Activity Relationship Data and Possible Agricultural Applications

2021 ◽  
Vol 7 (7) ◽  
pp. 539
Author(s):  
Tamás Plaszkó ◽  
Zsolt Szűcs ◽  
Gábor Vasas ◽  
Sándor Gonda
Keyword(s):  
Mycorrhizal Fungi ◽  
Current Knowledge ◽  
Synergistic Activity ◽  
Microbial Composition ◽  
Soil Microbial ◽  
Structure Activity ◽  
Agricultural Applications ◽  
Antifungal Action ◽  
Insight Into ◽  
Soil Microbial Composition

Plants heavily rely on chemical defense systems against a variety of stressors. The glucosinolates in the Brassicaceae and some allies are the core molecules of one of the most researched such pathways. These natural products are enzymatically converted into isothiocyanates (ITCs) and occasionally other defensive volatile organic constituents (VOCs) upon fungal challenge or tissue disruption to protect the host against the stressor. The current review provides a comprehensive insight on the effects of the isothiocyanates on fungi, including, but not limited to mycorrhizal fungi and pathogens of Brassicaceae. In the review, our current knowledge on the following topics are summarized: direct antifungal activity and the proposed mechanisms of antifungal action, QSAR (quantitative structure-activity relationships), synergistic activity of ITCs with other agents, effects of ITCs on soil microbial composition and allelopathic activity. A detailed insight into the possible applications is also provided: the literature of biofumigation studies, inhibition of post-harvest pathogenesis and protection of various products including grains and fruits is also reviewed herein.

Exact analysis of the bending of wide beams by a modified elastica approach

2011 ◽  
Vol 225 (11) ◽  
pp. 2759-2764 ◽  
Author(s):  
L F Campanile ◽  
R Jähne ◽  
A Hasse
Keyword(s):  
Finite Element ◽  
Substantial Reduction ◽  
Short Review ◽  
Computational Effort ◽  
Two Dimensional ◽  
Finite Element Calculations ◽  
Dimensional Finite Element ◽  
Wide Beams ◽  
Insight Into ◽  
Selection Of

Classical beam models do not account for partial restraint of anticlastic bending and are therefore inherently inaccurate. This article proposes a modification of the exact Bernoulli–Euler equation which allows for an exact prediction of the beam's deflection without the need of two-dimensional finite element calculations. This approach offers a substantial reduction in the computational effort, especially when coupled with a fast-solving schema like the circle-arc method. Besides the description of the new method and its validation, this article offers an insight into the somewhat disregarded topic of anticlastic bending by a short review of the published theories and a selection of representative numerical results.

Design and topological optimization of rear pressure bulkhead for a typical aircraft

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Marshal Thakran ◽  
Meenakshi ◽  
Jitender Sharma ◽  
Charles Gilbert Martin
Keyword(s):  
Numerical Analysis ◽  
Significant Influence ◽  
Design Methodology ◽  
Structural Integrity ◽  
Topological Optimization ◽  
Content Type ◽  
Iterative Design ◽  
Practical Implications ◽  
Insight Into ◽  
Selection Of

Purpose The purpose of this paper is to evaluate the model of a rear pressure bulkhead with different design optimizations to meet the pressurized cabin requirements of an aircraft. Design/methodology/approach This paper presents the results of the static analysis of a dome-shaped rear pressure bulkhead model designed in Catia-v5. Numerical analysis of model meshed in hyper-mesh and solved using Opti-Struct for iterative design optimizations. Findings All the iterative models are analyzed at 9 Psi. Rear pressure bulkhead designed with L-section stringer shows better results than the model optimized with T-section stringer for the same thickness. The model optimized with L-shaped stinger also reduces the weight of the bulkhead without affecting the structural integrity. Practical implications It has been concluded in this paper that the selection of specific shapes of the stringers shows a significant influence on weight reduction. Originality/value This paper provides a topical, technical insight into the design and development of a rear pressure bulkhead. It also outlines the future development of dome-shaped rear pressure bulkhead.

Pyridine moiety: An insight into recent advances in treatment of cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Rakesh Sahu ◽  
Rakhi Mishra ◽  
Rajnish Kumar ◽  
Salahuddin ◽  
Chandana Majee ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Heterocyclic Compounds ◽  
Antitumor Agents ◽  
Pyridine Moiety ◽  
Structure Activity ◽  
Wide Range ◽  
Global Health Issue ◽  
Effective Drugs ◽  
Published Research ◽  
Insight Into

: The incidence of cancer is increasing worldwide, affecting a vast majority of the human population. As new different anticancer agents are being developed now, the requirement is to deal somehow with them and evaluate their safety. Among them, pyridine based drugs are contributing a lot, as it is one of the imperative pharmacophores occurring synthetically as well as naturally in heterocyclic compounds, and having a wide range of therapeutic applications in the area of drug discovery, thereby offering many chances for further improvement in antitumor agents via acting onto numerous receptors of extreme prominence. Many pyridine derivatives have been reported to inhibit enzymes, receptors and many other targets for controlling and curing the global health issue of cancer. Nowadays, in combination with other moieties, researchers are focusing on the development of pyridine-based new derivatives for cancer treatment. Therefore, this review sheds light on the recent therapeutic expansions of pyridine together with its molecular docking, structure-activity-relationship, availability in the market, and a summary of recently patented and published research works that shall jointly help the scientists to produce effective drugs with the desired pharmacological activity.

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