scholarly journals Peptide Conjugates with Small Molecules Designed to Enhance Efficacy and Safety

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1855 ◽  
Author(s):  
Rongjun He ◽  
Brian Finan ◽  
John P. Mayer ◽  
Richard D. DiMarchi
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Molecular Diversity ◽  
Molecular Mechanisms ◽  
Design Synthesis ◽  
Therapeutic Modalities ◽  
Small Molecule Drugs ◽  
Therapeutic Outcomes ◽  
Oncologic Diseases ◽  
Dose Dependent

Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.

Identification of Four Key Biomarkers and Small Molecule Drugs Innasopharyngeal Carcinoma by Weighted Gene Co-expression Network Analysis

2020 ◽  
Author(s):  
Xi Pan ◽  
Jian-Hao Liu
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Tumor Stage ◽  
Functional Enrichment ◽  
Hub Genes ◽  
Therapeutic Goals ◽  
Small Molecule Drugs

Abstract Background Nasopharyngeal carcinoma (NPC) is a heterogeneous carcinoma that the underlying molecular mechanisms involved in the tumor initiation, progression, and migration are largely unclear. The purpose of the present study was to identify key biomarkers and small-molecule drugs for NPC screening, diagnosis, and therapy via gene expression profile analysis. Methods Raw microarray data of NPC were retrieved from the Gene Expression Omnibus (GEO) database and analyzed to screen out the potential differentially expressed genes (DEGs). The key modules associated with histology grade and tumor stage was identified by using weighted correlation network analysis (WGCNA). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of genes in the key module were performed to identify potential mechanisms. Candidate hub genes were obtained, which based on the criteria of module membership (MM) and high connectivity. Then we used receiver operating characteristic (ROC) curve to evaluate the diagnostic value of hub genes. The Connectivity map database was further used to screen out small-molecule drugs of hub genes. Results A total of 430 DEGs were identified based on two GEO datasets. The green gene module was considered as key module for the tumor stage of NPC via WGCNA analysis. The results of functional enrichment analysis revealed that genes in the green module were enriched in regulation of cell cycle, p53 signaling pathway, cell part morphogenesis. Furthermore, four DEGs-related hub genes in the green module were considered as the final hub genes. Then ROC revealed that the final four hub genes presented with high areas under the curve, suggesting these hub genes may be diagnostic biomarkers for NPC. Meanwhile, we screened out several small-molecule drugs that have provided potentially therapeutic goals for NPC. Conclusions Our research identified four potential prognostic biomarkers and several candidate small-molecule drugs for NPC, which may contribute to the new insights for NPC therapy.

Unravelling the mechanisms underpinning chemokine receptor activation and blockade by small molecules: a fine line between agonism and antagonism?

2007 ◽  
Vol 35 (4) ◽  
pp. 755-759 ◽  
Author(s):  
E. Wise ◽  
J.E. Pease
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Considerable Effort ◽  
G Protein Coupled ◽  
Migration Of Cells

Chemokines are a family of small basic proteins which induce the directed migration of cells, notably leucocytes, by binding to specific GPCRs (G-protein-coupled receptors). Both chemokines and their receptors have been implicated in a host of clinically important diseases, leading to the notion that antagonism of the chemokine–chemokine receptor network may be therapeutically advantageous. Consequently, considerable effort has been put into the development of small-molecule antagonists of chemokine receptors and several such compounds have been described in the literature. One curious by-product of this activity has been the description of several small-molecule agonists of the receptors, which are typically discovered following the optimization of lead antagonists. In this review we discuss these findings and conclude that these small-molecule agonists might be exploited to further our understanding of the molecular mechanisms by which chemokine receptors are activated.

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.

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.

scholarly journals Ranking small molecules by how much they preferentially inhibit the growth of cancer cell lines with either BRAF or KRAS oncogene mutations

2014 ◽  
Author(s):  
James Langham
Keyword(s):  
Growth Inhibition ◽  
Small Molecules ◽  
Cell Line ◽  
Cell Lines ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Braf Inhibitor ◽  
Data Set ◽  
Cytidine Analogs ◽  
Knowledge Of Cancer

We were interested in the question of whether it might be possible to use knowledge of cancer-related mutations in the cell lines of the NCI60 screening data set to identify small molecules that preferentially inhibit the growth of cell lines containing either BRAF or KRAS oncogene mutations. Our hypothesis was that this cell line mutation knowledge could help to identify small molecules that were more likely to preferentially inhibit growth of cell lines with a particular mutation. It seems that any such molecules might be further investigated to try to better understand the molecular mechanisms of growth inhibition. We defined a quantity, \(\text{Diff}_{\text{mut}}\), that estimates how much more a given small molecule inhibits cell lines with a mutation of interest than cell lines without that mutation. We ranked the small molecules in descending order of \(\text{Diff}_{\text{mut}}\) and then tried to explain whether the ranking of the highest ranked molecules made sense in terms of independent facts about these molecules. This method showed the BRAF inhibitor vemurafenib to be highly ranked in the BRAF ranking. The cytidine analog cytarabine was found to be highly ranked in the KRAS ranking. Other cytidine analogs were also found to be highly ranked with respect to KRAS.

scholarly journals Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiang Xie ◽  
Yi Chen ◽  
Huidan Tan ◽  
Bo Liu ◽  
Ling-Li Zheng ◽  
...  
Keyword(s):  
Natural Products ◽  
Cancer Therapy ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Natural Compounds ◽  
Therapeutic Effects ◽  
Therapeutic Benefits ◽  
Small Molecule Drugs

Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.

scholarly journals Identification of Core Genes Related to Progression and Prognosis of Hepatocellular Carcinoma and Small-Molecule Drug Predication

2021 ◽  
Vol 12 ◽  
Author(s):  
Nan Jiang ◽  
Xinzhuo Zhang ◽  
Dalian Qin ◽  
Jing Yang ◽  
Anguo Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Gene Expression Signature ◽  
Cox Regression Analysis ◽  
Small Molecule Drugs

BackgroundHepatocellular carcinoma (HCC) is one of the most leading causes of cancer death with a poor prognosis. However, the underlying molecular mechanisms are largely unclear, and effective treatment for it is limited. Using an integrated bioinformatics method, the present study aimed to identify the key candidate prognostic genes that are involved in HCC development and identify small-molecule drugs with treatment potential.Methods and ResultsIn this study, by using three expression profile datasets from Gene Expression Omnibus database, 1,704 differentially expressed genes were identified, including 671 upregulated and 1,033 downregulated genes. Then, weighted co-expression network analysis revealed nine modules are related with pathological stage; turquoise module was the most associated module. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses (KEGG) indicated that these genes were enriched in cell division, cell cycle, and metabolic related pathways. Furthermore, by analyzing the turquoise module, 22 genes were identified as hub genes. Based on HCC data from gene expression profiling interactive analysis (GEPIA) database, nine genes associated with progression and prognosis of HCC were screened, including ANLN, BIRC5, BUB1B, CDC20, CDCA5, CDK1, NCAPG, NEK2, and TOP2A. According to the Human Protein Atlas and the Oncomine database, these genes were highly upregulated in HCC tumor samples. Moreover, multivariate Cox regression analysis showed that the risk score based on the gene expression signature of these nine genes was an independent prognostic factor for overall survival and disease-free survival in HCC patients. In addition, the candidate small-molecule drugs for HCC were identified by the CMap database.ConclusionIn conclusion, the nine key gene signatures related to HCC progression and prognosis were identified and validated. The cell cycle pathway was the core pathway enriched with these key genes. Moreover, several candidate molecule drugs were identified, providing insights into novel therapeutic approaches for HCC.

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 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.

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