The interactions of small molecule with proteins play an important role for determining the effects of drugs which are mostly small molecules 40 in the human body. Designing a small molecule to bind to a proteinprotein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable proteinprotein interactions, the surface area of the interface it is often large, and the location of hot spots small regions suitable for drug binding. Department of biotechnology, indian institute of technology roorkee, roorkee 247667. Hoggard, yongqiang zhang, min zhang, vanja panic, john a.
Abstract the tandem brct domains tbrct of brca1 engage phosphoserine. These researchers describe their unique approaches, and share. Developing small molecules that modulate proteinprotein interactions is difficult, owing to issues such as the lack of welldefined binding pockets. The main focus is placed on synthetic approaches to such molecules, their. Pdf smallmolecule inhibitors of proteinprotein interactions. From the initial discovery of the existence of hot spots at ppi interfaces, it has been proposed that hot spots might provide the key for developing smallmolecule ppi inhibitors. The nrf2are pathway is an intrinsic mechanism of defense against oxidative stress. Ddo5936 disrupted the hsp90cdc37 ppi both in vitro and in.
Most known ppi small molecules are orthosteric inhibitors but many ppi sites may be fundamentally intractable to this approach. Though they play a fundamental role in many biological processes and almost all pathological conditions including cancer, diabetes, and autoimmune diseases, ppis remain underrepresented in drug discovery. Optimization by crystal structure analysis and in vitro binding assays yielded compounds capable of disrupting the interaction. A general framework for development and data analysis of competitive highthroughput screens for smallmolecule inhibitors of proteinprotein interactions by fluorescence polarization. The design of small molecule inhibitors of proteinprotein interactions, however, is a challenging area in medicinal chemistry. However, the identification of small molecules enabling us to effectively interrupt their interactions presents significant challenges. From a druggability perspective, it is encouraging that a computational analysis attempting to extract socalled smallmolecule inhibitor starting points smisps from proteinligand and proteinprotein complexes in the protein data bank pdb suggested that nearly half of all ppis may be susceptible to smallmolecule inhibition. Targeting proteinprotein interactions ppis remains one of the large challenges in drug discovery. Wisniewski, and haitao ji department of chemistry, center for cell and genome science, university of utah, salt lake city, utah 841120850, united states.
Here, we identified ddo5936 as a smallmolecule inhibitor of the hsp90cdc37 proteinprotein interaction ppi in colorectal cancer. The past 20 years have seen many advances in our understanding of proteinprotein interactions ppis and how to target them with smallmolecule therapeutics. Inthera bioscience employs a proprietary technology platform to rationally design small molecule inhibitors of intracellular proteinprotein interactions ppis. Proteinprotein interactions ppis are important targets for the development of chemical probes and therapeutic agents. Sharanya sarkar, khushboo gulati, manikyaprabhu kairamkonda, amit mishra and krishna mohan poluri affiliation. Smallmolecule inhibitors of proteinprotein interactions current topics in microbiology and immunology. These researchers describe their unique approaches, and share experiences, results, thoughts, and opinions. Proteinprotein interactions ppis are critical regulatory events in physiology and. Master of science, texas christian university, 2008. Targeting proteinprotein interactions ppis has emerged as a viable approach in modern drug discovery. However, isolation of ppi inhibitors is extremely challenging. Unlike enzymes or g proteincoupled receptors gpcrs, nature did not offer simple small molecules that can start a chemical discovery.
Stateoftheart strategies of targeting proteinprotein. Rapid online virtual screening for smallmolecule protein protein interaction inhibitors david r. Proteinprotein interactions represent a large and important class of targets for human therapeutics. Rational design of selective smallmolecule inhibitors for catenin bcell lymphoma 9 protein. The large and flat interacting surfaces of ppis make discovery of smallmolecule modulators a challenging task. Property focused structurebased optimization of small. Small molecule inhibitors of raseffector protein interactions. Small molecule inhibitors targeting new targets of protein. We report here the identification of nonacidic tetrahydroisoquinolines thiqs that inhibit the keap1nrf2 proteinprotein interaction. Another perceived problem with targeting protein protein interactions concerns the properties of potential smallmolecule inhibitors. Inthera biosciences approach to proteinprotein interactions. Optimization of direct small molecule inhibitors of keap1. Protein interactions using combined ligand and target score normalization.
Structurebased design and discovery of small molecule. Stateoftheart strategies of targeting proteinprotein interactions by smallmolecule inhibitors chunquan sheng,a, guoqiang dong,a zhenyuan miao, a wannian zhang a and wei wang b,c, targeting proteinprotein interactions ppis has emerged as viable approaches in modern drug discovery. Smallmolecule inhibitors of proteinprotein interactions protein. Targeting proteinprotein interaction by small molecules annual. The different interaction patterns are at least as important as. Selectivity by smallmolecule inhibitors of protein interactions can. New strategies and more effective chemical technologies are needed to facilitate the development of ppis smallmolecule inhibitors.
Nonetheless, progress continues to be made, resulting in clinical trials for six targets. Proteinprotein interactions ppis are a promising, but challenging target for pharmaceutical intervention. Rational design of selective smallmolecule inhibitors for. Until recently it has been believed that only truly small molecules, that is, those with m r. New targets of ppis were identified, and lots of small molecule modulators were developed. Pdf small molecule inhibitors of human papillomavirus. Stateoftheart strategies for targeting proteinprotein. However, developing smallmolecule antagonists of proteinprotein interactions is. Small molecule inhibitors of the human papillomavirus e1e2 interaction. Proteinprotein interactions ppis are fundamental to the growth and survival of cells and serve as excellent targets to develop inhibitors of biological processes such as hostpathogen interactions and cancer cell proliferation. A yeast genetic system for selecting small molecule inhibitors of proteinprotein interactions in nanodroplets jing huang and stuart l. Small molecule inhibitors of proteinprotein interactions by kareem khoury bachelor of science, university of pittsburgh, 2008 submitted to the graduate faculty of school of pharmacy in partial fulfillment of the requirements for the degree of doctor of philosophy university of pittsburgh 20. Small molecule inhibitors of proteinprotein interactions.
Combined peptide and smallmolecule approach toward. Targeting proteinprotein interactions by small molecule compounds is challenging. Modulating proteinprotein interactions is becoming an increasingly attractive strategy for the development of small molecule inhibitors, but remains a challenge due to various obstacles such as lack of welldefined binding pockets and the need to compete with large proteinprotein binding interfaces, etc. General aspects and recent progress in targeting costimulatory and coinhibitory immune checkpoint interactions. Smallmolecule inhibitors of proteinprotein interactions. We report first noncovalent and exclusively extracellular inhibitors of 1433 proteinprotein interactions identified by virtual screening. Proteinprotein interactions ppis that are part of the costimulatory and coinhibitory immune checkpoint signaling are critical for adequate t. In this regard, proteins function not merely as single, isolated entities, but display their roles by interacting with other cellular components. Targeting proteinprotein interaction by small molecules. Schreiber howard hughes medical institute, department of chemistry and chemical biology, harvard university, 12 oxford street, cambridge, ma 028 contributed by stuart l. Proteinprotein interactions as targets for smallmolecule. Elucidating proteinprotein interactions through computational approaches and designing small molecule inhibitors against them for various diseases volume.
Disrupting the interactions between hsp90 and cdc37 is emerging as an alternative and specific way to regulate the hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. While several in vitro assays to screen for ppi inhibitors are available, they are often expensive. Smallmolecule inhibitor starting points learned from. Proteinprotein interactions ppis are implicated in almost all biological processes for any given protein engaged in complexes with other proteins for themajority of its lifetime. While there is no doubt that these protein classes are. Screening of smallmolecule inhibitors of proteinprotein interaction. Targeting specific proteinprotein interactions ppis is an attractive concept for drug development, but hard to implement since intracellular antibodies. However, targeting ppis with small molecules is challenging owing to the large surface area involved in proteinprotein binding and the lack of obvious smallmoleculebinding pockets at many proteinprotein interfaces. Smallmolecule inhibition of the direct proteinprotein interactions that mediate many important. Screening of smallmolecule inhibitors of proteinprotein interaction with. Proteinprotein interactions ppis constitute a rising class of targets for the next generation of therapeutic intervention. Case studies of smallmolecule inhibitors of proteinprotein interactions. The majority of current fdaapproved small molecules target enzymes and cell surface receptors.
Pocket optimization and its application to identify small. Max planck institute of biochemistry, department of molecular biology, am klopferspitz 18, 82152 martinsried, germany, center for integrated protein science munich cipsm, germany. However, it has to be noted that for targets such as sh2 domains, proteases, and integrins, where interactions with the protein partner typically involve binding to an isolated peptide loop or strand and not to a broad protein surface, it is considerably easier to identify small. Discovery of small molecule inhibitors of proteinprotein interactions using combined ligand and. Hot spotbased design of smallmolecule inhibitors for. Small molecule targeting of proteinprotein interactions. Considering that the cellular potency or druglike properties of direct inhibitors have remained as significant factors to be overcome, we have focused on discovering diverse classes of potent small molecule inhibitors based on known compounds via two different rational approaches. This book covers the stateoftheart strategies developed for proteinprotein interaction ppi inhibitors, and highlights the success stories in new drug discovery and development.
Development of potent small molecule inhibitors of proteinprotein interactions with optimized druglike properties represents a challenging task in lead optimization process. Inhibition of the interaction between nrf2 and its main negative regulator keap1 is an attractive strategy toward neuroprotective agents. M dabramo and jacques archambault, booktitlethe open virology journal, year2011. Hydrogenbonded synthetic mimics of protein secondary structure as disruptors of proteinprotein interactions. In this volume, the editors have collected the knowledgeable insights of a number of leaders in this field researchers who have achieved success in addressing the difficult problem of inhibiting proteinprotein interactions. Targeting proteinprotein interaction with covalent small. Recent smallmolecule inhibitors of the p53mdm2 protein.
Proteinprotein interactions ppis are critical regulatory events in physiology and pathology, and they represent an important target space for pharmacological intervention. Modulating proteinprotein interactions is becoming an increasingly attractive strategy for the development of small molecule inhibitors, but remains a challenge due to various obstacles such as lack of welldefined binding pockets and the need to compete with. Here, we describe a genetic system compatible with splitpool synthesis that allows the detection of cellpermeable, small molecule inhibitors of proteinprotein interactions in 100 to 200nl cell culture droplets, prepared by a recently described technique that arrays large numbers of such droplets. A yeast genetic system for selecting small molecule. In the recent past, significant advances have been made in. One approach for addressing these difficult targets is the rational design of smallmolecule inhibitors that mimic the chemical and physical properties of small clusters of key residues at the proteinprotein interface. It demonstrates the design strategies and case studies of small molecule ppi inhibitors. Author summary despite intense interest and considerable effort, there are few examples of small molecules that directly inhibit proteinprotein. Pdf toward smallmolecule inhibition of proteinprotein.
This dissertation focuses on applying computational methods to design and discover small molecule inhibitors to target two proteinprotein interactions. Small molecule inhibitors of human papillomavirus protein. Smallmolecule inhibitor targeting the hsp90cdc37 protein. Camacho1 1department of computational and systems biology, university of pittsburgh, pittsburgh, pennsylvania 2department of drug design, university of groningen, groningen, the netherlands. Here, we report synthesis and structurebased optimization of new thienopyrimidine class of compounds, which block the proteinprotein interaction between menin and mll fusion proteins that plays an important role in. Targeting proteinprotein interactions by small molecules. Method for identifying small molecule inhibitors of the. Targeting specific proteinprotein interactions ppis is an attractive concept for drug. Toward smallmolecule inhibition of proteinprotein interactions.
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