scholarly journals Pharmacogenomics: An Update on Biologics and Small-Molecule Drugs in the Treatment of Psoriasis

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1398
Author(s):  
Valerio Caputo ◽  
Claudia Strafella ◽  
Terenzio Cosio ◽  
Caterina Lanna ◽  
Elena Campione ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Clinical Utility ◽  
Tumor Necrosis ◽  
Drug Efficacy ◽  
Dimethyl Fumarate ◽  
Biological Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor ◽  
Pharmacogenomic Studies

Pharmacogenomic studies allowed the reasons behind the different responses to treatments to be understood. Its clinical utility, in fact, is demonstrated by the reduction in adverse drug reaction incidence and the improvement of drug efficacy. Pharmacogenomics is an important tool that is able to improve the drug therapy of different disorders. In particular, this review will highlight the current pharmacogenomics knowledge about biologics and small-molecule treatments for psoriasis. To date, studies performed on genes involved in the metabolism of biological drugs (tumor necrosis factor inhibitors and cytokines inhibitors) and small molecules (apremilast, dimethyl fumarate, and tofacitinib) have provided conflicting results, and further investigations are necessary in order to establish a set of biomarkers to be introduced into clinical practice.

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

Fragment-based drug design of nature-inspired compounds

2019 ◽  
Vol 4 (9) ◽  
Author(s):  
Abdulkarim Najjar ◽  
Abdurrahman Olğaç ◽  
Fidele Ntie-Kang ◽  
Wolfgang Sippl
Keyword(s):  
Drug Design ◽  
Small Molecules ◽  
Small Molecule ◽  
Binding Pocket ◽  
Biological Macromolecules ◽  
Drug Candidates ◽  
Fragment Screening ◽  
Small Molecule Drugs ◽  
Lead Generation ◽  
Hit Identification

Abstract Natural product (NP)-derived drugs can be extracts, biological macromolecules, or purified small molecule substances. Small molecule drugs can be originally purified from NPs, can represent semisynthetic molecules, natural fragments containing small molecules, or are fully synthetic molecules that mimic natural compounds. New semisynthetic NP-like drugs are entering the pharmaceutical market almost every year and reveal growing interests in the application of fragment-based approaches for NPs. Thus, several NP databases were constructed to be implemented in the fragment-based drug design (FBDD) workflows. FBDD has been established previously as an approach for hit identification and lead generation. Several biophysical and computational methods are used for fragment screening to identify potential hits. Once the fragments within the binding pocket of the protein are identified, they can be grown, linked, or merged to design more active compounds. This work discusses applications of NPs and NP scaffolds to FBDD. Moreover, it briefly reviews NP databases containing fragments and reports on case studies where the approach has been successfully applied for the design of antimalarial and anticancer drug candidates.

Long-term Survival of Subcutaneous Anti-tumor Necrosis Factor Biological Drugs Administered Between 2008 and 2012 in a Cohort of Rheumatoid Arthritis Patients

2019 ◽  
Vol 15 (1) ◽  
pp. 54-57
Author(s):  
Noelia Alvarez Rivas ◽  
Tomas R. Vazquez Rodriguez ◽  
Jose A. Miranda Filloy ◽  
Carlos Garcia-Porrua ◽  
Amalia Sanchez-Andrade Fernández
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Biological Drugs ◽  
Term Survival ◽  
Long Term Survival ◽  
Necrosis Factor

scholarly journals Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

2020 ◽  
Vol 21 (15) ◽  
pp. 5262 ◽  
Author(s):  
Qingxin Li ◽  
CongBao Kang
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Structural Biology ◽  
Small Molecule ◽  
Molecular Interactions ◽  
Mechanisms Of Action ◽  
Rational Drug Design ◽  
Binding Modes ◽  
Small Molecule Drugs ◽  
Rational Drug

Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design.

scholarly journals An Innovative High-Throughput Screening Approach for Discovery of Small Molecules That Inhibit TNF Receptors

2017 ◽  
Vol 22 (8) ◽  
pp. 950-961 ◽  
Author(s):  
Chih Hung Lo ◽  
Nagamani Vunnam ◽  
Andrew K. Lewis ◽  
Ting-Lan Chiu ◽  
Benjamin E. Brummel ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Ligand Binding ◽  
Small Molecules ◽  
High Throughput ◽  
High Throughput Screening ◽  
Tumor Necrosis ◽  
Critical Role ◽  
Receptor Activation ◽  
Computational Docking ◽  
Necrosis Factor

Tumor necrosis factor receptor 1 (TNFR1) is a transmembrane receptor that binds tumor necrosis factor or lymphotoxin-alpha and plays a critical role in regulating the inflammatory response. Upregulation of these ligands is associated with inflammatory and autoimmune diseases. Current treatments reduce symptoms by sequestering free ligands, but this can cause adverse side effects by unintentionally inhibiting ligand binding to off-target receptors. Hence, there is a need for new small molecules that specifically target the receptors, rather than the ligands. Here, we developed a TNFR1 FRET biosensor expressed in living cells to screen compounds from the NIH Clinical Collection. We used an innovative high-throughput fluorescence lifetime screening platform that has exquisite spatial and temporal resolution to identify two small-molecule compounds, zafirlukast and triclabendazole, that inhibit the TNFR1-induced IκBα degradation and NF-κB activation. Biochemical and computational docking methods were used to show that zafirlukast disrupts the interactions between TNFR1 pre-ligand assembly domain (PLAD), whereas triclabendazole acts allosterically. Importantly, neither compound inhibits ligand binding, proving for the first time that it is possible to inhibit receptor activation by targeting TNF receptor–receptor interactions. This strategy should be generally applicable to other members of the TNFR superfamily, as well as to oligomeric receptors in general.

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