Targeted protein degradation and regulation with molecular glue: past and recent discoveries

2021 ◽  
Vol 28 ◽  
Author(s):  
Yizheng Fang ◽  
Qiaojun He ◽  
Ji Cao
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Small Molecules ◽  
Mechanisms Of Action ◽  
Clinical Settings ◽  
Protein Protein Interaction ◽  
Protein Inhibition ◽  
The Past ◽  
New Methods ◽  
Disease Associated Genes

: The evolution in research and clinical settings of targeted therapies has been inspired by the progress of cancer chemotherapy to use small molecules and monoclonal antibodies for targeting specific disease-associated genes and proteins for noninfectious chronic diseases. In addition to conventional protein inhibition and activation strategies as drug discovery modalities, new methods of targeted protein degradation and regulation using molecular glues have become an attractive approach for drug discovery. Mechanistically, molecular glues trigger interactions between the proteins that originally did not interact by forming ternary complexes as protein-protein interaction (PPI) modulators. New molecular glues and their mechanisms of action have been actively investigated in the past decades. An immunomodulatory imide drug, thalidomide, and its derivatives have been used in the clinic and are a class of molecular glue that induces degradation of several neo-substrates. In this review, we summarize the development of molecular glues and share our opinions on the identification of novel molecular glues in an attempt to promote the concept and inspire further investigations.

Targeted Protein Degradation: "The Gold Rush is On!"

2020 ◽  
Vol 7 (1) ◽  
pp. 4-16
Author(s):  
Daria Kotlarek ◽  
Agata Pawlik ◽  
Maria Sagan ◽  
Marta Sowała ◽  
Alina Zawiślak-Architek ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Small Molecule ◽  
Gold Rush ◽  
European Company ◽  
Drug Candidates ◽  
Protein Inhibition ◽  
Small Molecule Drug ◽  
Therapeutic Benefits ◽  
Talent Pool

Targeted Protein Degradation (TPD) is an emerging new modality of drug discovery that offers unprecedented therapeutic benefits over traditional protein inhibition. Most importantly, TPD unlocks the untapped pool of the proteome that to date has been considered undruggable. Captor Therapeutics (Captor) is the fourth global, and first European, company that develops small molecule drug candidates based on the principles of targeted protein degradation. Captor is located in Basel, Switzerland and Wroclaw, Poland and exploits the best opportunities of the two sites – experience and non-dilutive European grants, and talent pool, respectively. Through over $38 M of funding, Captor has been active in three areas of TPD: molecular glues, bi-specific degraders and direct degraders, ObteronsTM.

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

2016 ◽  
Vol 15 (8) ◽  
pp. 533-550 ◽  
Author(s):  
Duncan E. Scott ◽  
Andrew R. Bayly ◽  
Chris Abell ◽  
John Skidmore
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Interaction ◽  
Protein Protein Interaction

scholarly journals SMALL MOLECULES SOLVING BIG PROBLEMS: PRESENT AND FUTURE OF DRUG DISCOVERY

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Anna Lucia Fallacara ◽  
Iuni Margaret Laura Tris ◽  
Amalia Belfiore ◽  
Maurizio Botta
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Small Molecules ◽  
Rational Design ◽  
Development Process ◽  
New Drugs ◽  
Drug Development Process ◽  
Development Models ◽  
The Past ◽  
The Cost

The Drug development process has undergone a great change over the years. The way, from haphazard discovery of new natural products with a potent biological activity to a rational design of small molecule effective against a selected target, has been long and sprinkled with difficulties. The oldest drug development models are widely perceived as opaque and inefficient, with the cost of research and development continuing to rise even if the production of new drugs remains constant. The present paper, will give an overview of the principles, approaches, processes, and status of drug discovery today with an eye towards the past and the future.

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 Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Haiying Lu ◽  
Qiaodan Zhou ◽  
Jun He ◽  
Zhongliang Jiang ◽  
Cheng Peng ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Small Molecules ◽  
Protein Interactions ◽  
Clinical Studies ◽  
New Drugs ◽  
Protein Protein Interactions ◽  
The Past ◽  
Recent Advances ◽  
Novel Drugs

Abstract Protein–protein interactions (PPIs) have pivotal roles in life processes. The studies showed that aberrant PPIs are associated with various diseases, including cancer, infectious diseases, and neurodegenerative diseases. Therefore, targeting PPIs is a direction in treating diseases and an essential strategy for the development of new drugs. In the past few decades, the modulation of PPIs has been recognized as one of the most challenging drug discovery tasks. In recent years, some PPIs modulators have entered clinical studies, some of which been approved for marketing, indicating that the modulators targeting PPIs have broad prospects. Here, we summarize the recent advances in PPIs modulators, including small molecules, peptides, and antibodies, hoping to provide some guidance to the design of novel drugs targeting PPIs in the future.

scholarly journals Macrocycles as protein–protein interaction inhibitors

2017 ◽  
Vol 474 (7) ◽  
pp. 1109-1125 ◽  
Author(s):  
Patrick G. Dougherty ◽  
Ziqing Qian ◽  
Dehua Pei
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Cyclic Peptides ◽  
Macrocyclic Compounds ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
Drug Candidates ◽  
Protein Protein Interaction ◽  
The Past ◽  
Conventional Drug

Macrocyclic compounds such as cyclic peptides have emerged as a new and exciting class of drug candidates for inhibition of intracellular protein–protein interactions, which are challenging targets for conventional drug modalities (i.e. small molecules and proteins). Over the past decade, several complementary technologies have been developed to synthesize macrocycle libraries and screen them for binding to therapeutically relevant targets. Two different approaches have also been explored to increase the membrane permeability of cyclic peptides. In this review, we discuss these methods and their applications in the discovery of macrocyclic compounds against protein–protein interactions.

scholarly journals InterLig: improved ligand-based virtual screening using topologically independent structural alignments

2020 ◽  
Vol 36 (10) ◽  
pp. 3266-3267
Author(s):  
Claudio Mirabello ◽  
Björn Wallner
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Small Molecules ◽  
Supplementary Information ◽  
Scaffold Hopping ◽  
Supplementary Data ◽  
Protein Target ◽  
The Past ◽  
3D Methods ◽  
Structural Alignments

Abstract Motivation In the past few years, drug discovery processes have been relying more and more on computational methods to sift out the most promising molecules before time and resources are spent to test them in experimental settings. Whenever the protein target of a given disease is not known, it becomes fundamental to have accurate methods for ligand-based virtual screening, which compares known active molecules against vast libraries of candidate compounds. Recently, 3D-based similarity methods have been developed that are capable of scaffold hopping and to superimpose matching molecules. Results Here, we present InterLig, a new method for the comparison and superposition of small molecules using topologically independent alignments of atoms. We test InterLig on a standard benchmark and show that it compares favorably to the best currently available 3D methods. Availability and implementation The program is available from http://wallnerlab.org/InterLig. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals The Development of Drugs against Acanthamoeba Infections

2016 ◽  
Vol 60 (11) ◽  
pp. 6441-6450 ◽  
Author(s):  
Ruqaiyyah Siddiqui ◽  
Yousuf Aqeel ◽  
Naveed Ahmed Khan
Keyword(s):  
Drug Discovery ◽  
Pharmaceutical Industry ◽  
Contact Lens ◽  
Contact Lenses ◽  
Mechanisms Of Action ◽  
The Other ◽  
Morbidity And Mortality ◽  
Content Type ◽  
Rate Of Development ◽  
The Past

ABSTRACTFor the past several decades, there has been little improvement in the morbidity and mortality associated withAcanthamoebakeratitis andAcanthamoebaencephalitis, respectively. The discovery of a plethora of antiacanthamoebic compounds has not yielded effective marketed chemotherapeutics. The rate of development of novel antiacanthamoebic chemotherapies of translational value and the lack of interest of the pharmaceutical industry in developing such chemotherapies have been disappointing. On the other hand, the market for contact lenses/contact lens disinfectants is a multi-billion-dollar industry and has been successful and profitable. A better understanding of drugs, their targets, and mechanisms of action will facilitate the development of more-effective chemotherapies. Here, we review the progress toward phenotypic drug discovery, emphasizing the shortcomings of useable therapies.

scholarly journals InterLig: a fast and accurate software for ligand-based virtual screening

2019 ◽  
Author(s):  
Claudio Mirabello ◽  
Björn Wallner
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Small Molecules ◽  
Open Source ◽  
Computational Methods ◽  
New Method ◽  
Scaffold Hopping ◽  
Protein Target ◽  
The Past ◽  
3D Methods

AbstractIn the past few years, drug discovery processes have been relying more and more on computational methods to sift out the most promising molecules before time and resources are spent to test them in experimental settings. Whenever the protein target of a given disease is not known, it becomes fundamental to have accurate methods for ligand-based Virtual Screening, which compare known active molecules against vast libraries of candidate compounds. Recently, 3D-based similarity methods have been developed that are capable of scaffold-hopping and to superimpose matching molecules. Here, we present InterLig, a new method for the comparison and superposition of small molecules based on 3D, topologically-independent alignments of atoms. We test InterLig on a standard benchmark and show that it compares favorably to the best currently available 3D methods.InterLig is open source and is available to everyone at: http://wallnerlab.org/interlig.

scholarly journals Assays and technologies for developing proteolysis targeting chimera degraders

2020 ◽  
Author(s):  
Xingui Liu ◽  
Xuan Zhang ◽  
Dongwen Lv ◽  
Yaxia Yuan ◽  
Guangrong Zheng ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Small Molecules ◽  
Rational Design ◽  
Degradation Pathway ◽  
New Techniques ◽  
Design And Optimization ◽  
Structure Activity ◽  
Ubiquitin Proteasome ◽  
Complicated Mechanism

Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small molecules that can recruit an E3 ligase and a protein of interest (POI) into proximity, leading to induced ubiquitination and degradation of the POI by the proteasome system. To date, the design and optimization of PROTACs remain empirical due to the complicated mechanism of induced protein degradation. Nevertheless, it is increasingly appreciated that profiling step-by-step along the ubiquitin-proteasome degradation pathway using biochemical and biophysical assays are essential in understanding the structure–activity relationship and facilitating the rational design of PROTACs. This review aims to summarize these assays and to discuss the potential of expanding the toolbox with other new techniques.

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