I've updated the hit identification section of the Drug Discovery Resources. In particular I've added to the high-throughput screening analysis including more information on PAINS (Pan Assay Interference Compounds) first described by Baell et al DOI and subsequently summarised in an excellent Nature comment.
Academic researchers, drawn into drug discovery without appropriate guidance, are doing muddled science. When biologists identify a protein that contributes to disease, they hunt for chemical compounds that bind to the protein and affect its activity. A typical assay screens many thousands of chemicals. ‘Hits’ become tools for studying the disease, as well as starting points in the hunt for treatments.
These molecules — pan-assay interference compounds, or PAINS — have defined structures, covering several classes of compound. But biologists and inexperienced chemists rarely recognize them. Instead, such compounds are reported as having promising activity against a wide variety of proteins. Time and research money are consequently wasted in attempts to optimize the activity of these compounds. Chemists make multiple analogues of apparent hits hoping to improve the ‘fit’ between protein and compound. Meanwhile, true hits with real potential are neglected.
Also added a page on Aggregators. Promiscuous inhibition caused by small molecule aggregation is a major source of false positive results in high-throughput screening. To mitigate this, use of a nonionic detergent such as Triton X-100 or Tween-80 has been studied, which can disrupt aggregates, and is now common in screening campaigns DOI.
The Handbook of Medicinal Chemistry is a new book providing insight and advice for medicinal chemists.
Drug discovery is a constantly developing and expanding area of research. Developed to provide a comprehensive guide, the Handbook of Medicinal Chemistry covers the past, present and future of the entire drug development process. Highlighting the recent successes and failures in drug discovery, the book helps readers to understand the factors governing modern drug discovery from the initial concept through to a marketed medicine. With chapters covering a wide range of topics from drug discovery processes and optimization, development of synthetic routes, pharmaceutical properties and computational biology, the handbook aims to enable medicinal chemists to apply their academic understanding to every aspect of drug discovery. Each chapter includes expert advice to not only provide a rigorous understanding of the principles being discussed, but to provide useful hints and tips gained from within the pharmaceutical industry. This expertise, combined with project case studies, highlighting and discussing all areas of successful projects, make this an essential handbook for all those involved in pharmaceutical development.
A free app has also been created in collaboration with the editors of the book. The Medicinal Chemistry Toolkit provides a suite of resources to support the day to day work of a medicinal chemist
I've been working with the BioFocus group at Chesterford Park (now part of Charles River) thinking about ligands for Protein Protein Interactions, some of the work was described on a poster at the 18th Cambridge Medicinal Chemistry Meeting held in Cambridge in September this year. The poster is now available online http://www.criver.com/files/pdfs/nonsource/do-privileged-ppi-scaffolds-exist.aspx
Protein-protein interactions (PPIs) are ubiquitous in cellular biochemistry; however they are often difficult drug targets to interrogate due to their unique molecular topologies. A consequence is that low hit rates are frequently observed in PPI HTS campaigns and there remains an unmet need for innovative small molecule PPI inhibitors (SMPPIIs). The term "privileged scaffold" was coined in 1988 when core structures were found to bind to more than one receptor with high affinity. This led us to pose the question: “Do privileged PPI scaffolds exist?”
A brilliant group of scientists to work with, many stimulating discussions in a very important area.
Cancer Research UK has a series of 7 grand challenges detailed on its website
Challenge 1: Develop vaccines to prevent non-viral cancers
Challenge 2: Eradicate EBV-induced cancers from the world
Challenge 3: Identify new targets for cancer prevention by understanding how unusual patterns of mutation are induced by different cancer-causing events
Challenge 4: Distinguish between lethal cancers that need treating, and non-lethal cancers that don’t
Challenge 5: Map the molecular and cellular tumour microenvironment in order to define new targets for therapy and prognosis
Challenge 7: Deliver biologically active macromolecules to any and all cells in the body to effectively treat cancer
Well worth reading about and there is also the opportunity to suggest your own challenge.
Here are the slides for a talk I gave at the Cambridge Cheminformatics Network Meeting in August.
P. Patrizia Mangione, Stéphanie Deroo, Stephan Ellmerich, Vittorio Bellotti, Simon Kolstoe, Stephen P. Wood, Carol V. Robinson, Martin D. Smith, Glenys A. Tennent, Robert J. Broadbridge, Claire E. Council, Joanne R. Thurston, Victoria A. Steadman, Antonio K. Vong, Christopher J. Swain, Mark B. Pepys, Graham W. Taylor
Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR–ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.
Aggregation is a regular concern when evaluating potential hits from screening and a recent paper "An Aggregation Advisor for Ligand Discovery" DOI attempts to provide an insight into this phenomenon, in addition they provide a useful web-based tool http://advisor.bkslab.org that provides a free service to advise whether molecules may aggregate under biological assay conditions.
There are between 5,000 and 8,000 rare diseases, and around 5 new rare diseases are described in the literature each week. There is no internationally recognised definition of a rare disease but they are defined by the European Union as one that affects less than 5 in 10,000 of the general population. Most rare diseases have a genetic component and if apparent in early life a significant number die before their 5th birthday. Reportedly only around 400 rare diseases have therapies and so I was interested to hear about The UK Strategy for Rare Diseases, if you have time it is an interesting read. The focus is more on the clinical side but the recognition of the need for robust epidemiological analysis and coordination of research activities of the major research funders is highlighted.
Changes in the Pharma industry have thrown into sharp focus the role of medicinal chemists, the European Federation for Medicinal Chemistry (EFMC) have now published a position paper defining the role of medicinal chemistry.
Medicinal chemistry is concerned with the design and synthesis of biologically active molecules. It aims at creating new chemical structures to better understand and influence physiological and/or pathological systems. Ultimately, it allows the discovery and optimization of novel drug candidates to address unmet medical needs, as exemplified by recent progress in the treatment of cancer, cardiovascular or infectious diseases.
You can read the full paper here.