Small molecules, big targets: drug discovery faces the protein–protein interaction challenge

Scott, D.E.; Bayly, Andrew R.; Abell, C.; Skidmore, John

doi:10.1038/nrd.2016.29

Cited by 923 publications

(850 citation statements)

References 171 publications

Supporting

Mentioning

812

Contrasting

Unclassified

Order By: Relevance

“…We believe that TEX101-DPEP3 complex may provide an alternative target to develop nonhormonal male contraceptives. Even though disruption of PPIs by small molecules or short peptides is challenging, it is not impossible (78). The ultimate male germ cell specificity of TEX101 and DPEP3 proteins would minimize potential side effects.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

Schiza

Korbakis

Panteleli

et al. 2018

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

TEX101 is a testis-specific protein expressed exclusively in male germ cells and is a validated biomarker of male infertility. Studies in mice suggest that TEX101 is a cell-surface chaperone which regulates, through protein-protein interactions, the maturation of proteins involved in spermatozoa transit and oocyte binding. Male TEX101-null mice are sterile. Here, we identified by co-immunoprecipitation-mass spectrometry the interactome of human TEX101 in testicular tissues and spermatozoa. The testis-specific cell-surface dipeptidase 3 (DPEP3) emerged as the top hit. We further validated the TEX101-DPEP3 complex by using hybrid immunoassays.Combinations of antibodies recognizing different epitopes of TEX101 and DPEP3 facilitated development of a simple immunoassay to screen for disruptors of TEX101-DPEP3 complex. As a proof-of-a-concept, we demonstrated that anti-TEX101 antibody T4 disrupted the native TEX101-DPEP3 complex. Disrupting antibodies may be used to study the human TEX101-DPEP3 complex, and to develop modulators for male fertility.

show abstract

Section: Discussionmentioning

confidence: 99%

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

Schiza

Korbakis

Panteleli

et al. 2018

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…114 A broad range of different peptidomimetics have been developed, and their use has become a standard tool in medicinal chemistry and drug research today. 115 The field can be broadly divided into three categories, involving scaffold-based peptidomimetics as well as local and global modifications of the parent peptide. The aim of peptidomimetic design is to either maintain or improve biological activity, increase selectivity and most importantly, increase proteolytic stability.…”

Section: Peptidomimeticsmentioning

confidence: 99%

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

et al. 2016

View full text Add to dashboard Cite

The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry and the construction of 2 electronic devices. This review discusses the mechanism, scope and applications of the RuAAC reaction, covering the literature during the last 10 years. CONTENTS

show abstract

“…BRD4, ING1, and PHF6) contribute to abnormal gene expression programs and thus participate in cancer development making them interesting drug targets [2]. However, targeting PPIs has proven to be more challenging than targeting enzymes leading to the prevailing notion that they are not "druggable" [19,20]. The level of difficulty in developing PPI inhibitors is depends on the type of the two interacting proteins.…”

Section: Introductionmentioning

confidence: 99%

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

Young

Chang

2017

MOJBB

View full text Add to dashboard Cite

Cancer is associated with epigenetic changes such as abnormal DNA methylation and histone tail modifications, and these changes result in tumor suppressor gene silencing, oncogene overexpression, and genome instability -phenomena that are closely linked to cancer development. The epigenetic marks on DNA and histones are reversible and therefore it is possible to restore normal patterns through chemically targeting epigenetic regulators that generate, maintain, recognize, and remove these marks. In recent years, fragment-based drug discovery (FBDD) has been used to target both the protein-protein interactions (PPI) as well as the enzymatic functions of epigenetic factors. Low molecular weight fragments (MW<300) efficiently sample chemical space and can bind to discreet binding pockets on target proteins such as those found on PPI interface. In this review, we describe the biophysical, biochemical, and in silico methods used for FBDD. We also discuss the examples of using FBDD to target epigenetic readers such as bromodomain-containing proteins and epigenetic enzymes such as arginine methyltransferases 6 (PRMT6), lysine demethylase 4 (KDM4), and Sirtuin 2 (SIRT2). FBDD provides an economical alternative to traditional high throughput screening. Effective FBDD endeavors depend heavily on gaining structural information of ligand-protein interactions early on and the close collaboration between biophysicists, chemists, and biologists in all stages of the drug discovery process. Using FBDD, protein-protein interactions in non-enzymatic epigenetic factors can potentially be chemically modulated. Furthermore, FBDD enables the identification of new binding pockets that can improve compound specificity against various epigenetic enzymes.

show abstract

Small molecules, big targets: drug discovery faces the protein–protein interaction challenge

Cited by 923 publications

References 171 publications

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

Contact Info

Product

Resources

About