Structure and activity relationships of tartrate-based TACE inhibitors

Popovici‐Muller, Janeta; Belanger, David; Caldwell, John P.; Dai, Chaoyang; David, M.-H.; Girijavallabhan, Vinay; Lavey, Brian J.; Lee, Joe F.; Liu, Zhidan; Mazzola, Rob; Rizvi, Razia; Rösner, K; Shankar, B. B.; Spitler, Jim; Ting, Pauline C.; Vaccaro, Henry; Yu, Wei; Zhou, Guowei; Zhu, Zhiwei; Niu, Xiaoda; Sun, Jing; Guo, Zhuyan; Orth, Peter; Chen, Shiying; Kozlowski, Joseph A.; Lundell, Daniel; Madison, Vincent; McKittrick, Brian A.; Piwinski, John J.; Shih, Neng‐Yang; Shipps, Gerald W.; Siddiqui, M. Arshad; Strickland, Corey

doi:10.1016/j.bmcl.2010.06.104

Cited by 15 publications

(10 citation statements)

References 14 publications

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“…The molecular docking studies were performed using Molecular Operating Environment (MOE, 2015.10) software. In the Protein data bank (PDB), there are more than 23 crystal structure for ADAM17 co-crystallized with different substrates and inhibitors [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. To deeply investigate the binding affinity of vitamin D3 toward ADAM17 protein, we have performed extensive molecular modelling studies for vitamin D3 toward the different available crystal structures of ADAM17 protein.…”

Section: In Silico Molecular Modelling Studymentioning

confidence: 99%

Vitamin D3 Prevents the Deleterious Effects of Testicular Torsion on Testis by Targeting miRNA-145 and ADAM17: In Silico and In Vivo Study

et al. 2021

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Testicular torsion (TT) is the most common urological emergency in children and young adults that can lead to infertility in many cases. The ischemia-reperfusion (IR) injury due to TT has been implicated in the pathogenesis of testicular damage. The main pathological mechanisms of contralateral injury after ipsilateral TT are not fully understood. In the presented study, we investigated the molecular and microscopic basis of ipsilateral and contralateral testicular injury following ipsilateral testicular torsion detorsion (T/D) and explored the possible protective role of vitamin D3. The biochemical analysis indicated that IR injury following T/D significantly decreased the activity of testicular glutathione peroxidase (GPx) enzyme, level of serum testosterone, serum inhibin B, and expression of testicular miRNA145, while increased the activity of testicular myeloperoxidase (MPO) enzyme, level of testicular malondialdehyde (MDA), level of serum antisperm-antibody (AsAb), and expression of ADAM-17. The histological and semen analysis revealed that torsion of the testis caused damages on different tissues in testis. Interestingly, administration of vitamin D3 prior to the IR injury reversed the deterioration effect of IR injury on the testicular tissues as indicated by biochemical and histological analysis which revealed normal appearance of the seminiferous tubules with an apparent decrease in collagen fiber deposition in both ipsilateral and contralateral testes. Our results revealed that the protective effect of vitamin D3 treatment could be attributed to target miRNA145 and ADAM17 protein. To further investigate these findings, we performed a detailed molecular modelling study in order to explore the binding affinity of vitamin D3 toward ADAM17 protein. Our results revealed that vitamin D3 has the ability to bind to the active site of ADAM17 protein via a set of hydrophobic and hydrophilic interactions with high docking score. In conclusion, this study highlights the protective pharmacological application of vitamin D3 to ameliorate the damages of testicular T/D on the testicular tissues via targeting miRNA145 and ADAM17 protein.

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Section: In Silico Molecular Modelling Studymentioning

confidence: 99%

Vitamin D3 Prevents the Deleterious Effects of Testicular Torsion on Testis by Targeting miRNA-145 and ADAM17: In Silico and In Vivo Study

et al. 2021

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“…597 ADAMi-9 has a K i value of 0.86 nM and is selective over MMPs and ADAM-10. 581 To increase the bioavailability of this scaffold, 2-heteroaryl-substituted pyrrolidines were added. 582 One such derivative is ADAMi-10, which maintains selectivity over ADAM-10, has an inhibition constant of 5 nM, and has improved oral bioavailability as compared to earlier tartrate inhibitors.…”

Section: Chemical Reviewsmentioning

confidence: 99%

“…The tartrate group binds in an unusual tridentate fashion to the Zn 2+ ion (Figure ). ADAMi-9 has a K i value of 0.86 nM and is selective over MMPs and ADAM-10 . To increase the bioavailability of this scaffold, 2-heteroaryl-substituted pyrrolidines were added .…”

Section: Peptidases (Ec 34)mentioning

confidence: 99%

Targeting Metalloenzymes for Therapeutic Intervention

et al. 2018

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Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention. Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs. In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets.

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“…Protein BLAST analysis in the 3D protein structure database showed that neither the 3D protein structure of mature ADAM17 (full length), nor the extracellular domain is resolved experimentally. In contrast to the full protein and the extracellular domain, there are several resolved structures describing the catalytic domain with different inhibitors [37,[62][63][64][65][66][67][68][69][70][71][72][73][74]. It was observed that residues 215-672 belong to extracellular domain which is the potential domain for therapeutic targeting (Text S2).…”

Section: D Protein Structure Modeling and Molecular Docking 421 Struc...mentioning

confidence: 99%

In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators

Bienstein

Minond

Schwaneberg

et al. 2022

IJMS

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Understanding the mechanisms of modulators’ action on enzymes is crucial for optimizing and designing pharmaceutical substances. The acute inflammatory response, in particular, is regulated mainly by a disintegrin and metalloproteinase (ADAM) 17. ADAM17 processes several disease mediators such as TNFα and APP, releasing their soluble ectodomains (shedding). A malfunction of this process leads to a disturbed inflammatory response. Chemical protease inhibitors such as TAPI-1 were used in the past to inhibit ADAM17 proteolytic activity. However, due to ADAM17′s broad expression and activity profile, the development of active-site-directed ADAM17 inhibitor was discontinued. New ‘exosite’ (secondary substrate binding site) inhibitors with substrate selectivity raised the hope of a substrate-selective modulation as a promising approach for inflammatory disease therapy. This work aimed to develop a high-throughput screen for potential ADAM17 modulators as therapeutic drugs. By combining experimental and in silico methods (structural modeling and docking), we modeled the kinetics of ADAM17 inhibitor. The results explain ADAM17 inhibition mechanisms and give a methodology for studying selective inhibition towards the design of pharmaceutical substances with higher selectivity.

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Structure and activity relationships of tartrate-based TACE inhibitors

Cited by 15 publications

References 14 publications

Vitamin D3 Prevents the Deleterious Effects of Testicular Torsion on Testis by Targeting miRNA-145 and ADAM17: In Silico and In Vivo Study

Vitamin D3 Prevents the Deleterious Effects of Testicular Torsion on Testis by Targeting miRNA-145 and ADAM17: In Silico and In Vivo Study

Targeting Metalloenzymes for Therapeutic Intervention

In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators

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