Therapeutically Relevant Bioassays – CDD Webinar
December 20, 2016
We’re delighted to share with you the slides and transcript from our exciting “Therapeutically Relevant Bioassays” Webinar:
Dr. Nathan Coussens discusses best practices and Professor Paul Roepe (Georgetown) tackles the problem of therapeutically relevant bioassays given the complexity of Malaria biology.
- Nathan Coussens, Senior Research Scientist, Biology, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
- Paul Roepe, Professor of Chemistry, Professor of Biochemistry & Cell. and Mol. Biol., Co-director, Center for Infectious Disease, Georgetown University
Transcript with slide positions in parenthesis:
Kellan: (#1) Thank you all for joining our webinar. The technologies and methods that our esteemed panelists will discuss with you today are critical for the quality, reproducibility and therapeutic relevance of assays. Understanding biology is the foundation for creating useful protocols, and of course useful (#2) protocols let us better understand the biology. With the Assay Guidance Manual from Nathan, we will look at an important resource for researchers offering best practices and guidelines, and then Professor Roepe will guide us through interesting examples for discovering anti-malarials.
Frank: (#3) GoToWebinar offers you a Question panel where you can pose your questions for our panelists that we will get to at the end of our discussions. Please pose a question at anytime – And again we are joined by Nathan Coussens, Sr Research Scientist from NIH’s NCATS and Paul Roepe, Professor and Co-director, Center for Infectious Disease, Georgetown University. Thanks for joining us. … let me launch our discussion by going to Nathan…
Nathan, Tell us about your research background and experiences at NCI, NCATS, and elsewhere?
As an undergraduate, I studied biochemistry at the University of Iowa and quickly became involved in research laboratories located throughout the campus. My first experience involved endocrine research in the laboratory of Dr. Eugene Spaziani in the Department of Biology and I have continued to collaborate- to this day- with one of his colleagues, Dr. Barbara Stay. I spent a year in the psychology department assisting Dr. John Freeman with experiments to study the neurobiology of learning and memory. At that time I was very interested in protein structure and function and joined the laboratory of Dr. Ramaswamy Subramanian in the department of biochemistry. Rams has really diverse research interests and his lab uses a variety of biophysical approaches to understand protein structure and function. The wonderful experience I had while working in his lab is what made me really want to pursue a career in research and I ended up doing my graduate studies in Rams’ lab. Primarily my graduate research focused on the innate immune system and host-pathogen interactions. While I waited for my wife to finish school, I spent an additional year at Iowa as a postdoc and collaborated with Dr. Michael Apicella’s lab in the department of microbiology to develop small molecule inhibitors of a host evasion mechanism in pathogenic bacteria that his lab discovered.
As a postdoc, I wanted to expand my skill set and investigate protein structure and function on a larger scale. Signaling of the immune system involves multiprotein complexes that can be quite large, but below the scale of organelles. These structures are critical for proper biological function but are extremely challenging to study, because such structures can be highly dynamic both in composition as well as their spatial and temporal assembly. I carried out my postdoctoral studies investigating signaling complexes in the laboratory of Dr. Larry Samelson at the National Cancer Institute, who is one of the world’s experts in T cell signaling. It was an incredible experience and research environment. His lab is well known for using cutting-edge technologies and taking very diverse approaches to the study of signaling in T cells. Ultimately I was interested in a research career in the pharmaceutical industry and I was doing a lot to investigate career opportunities towards the end of my postdoctoral training.
I participated in a tremendous program offered by the NIH called the Translational Science Training Program, which is a multi-day “boot camp” that covers the entire bench-to-bedside process. During this program, we were able to tour NCATS before it became an official center of the NIH. I felt strongly that the mission of NCATS is incredibly important and exciting and I was later hired on as a staff scientist. At NCATS I have been able to draw heavily from my diverse scientific training in developing biologically and physiologically relevant biochemical and cell-based assays for a variety of human diseases. Many of the folks that work at NCATS came from the pharmaceutical industry and I knew that I was missing some critical experience not having that background. I was delighted that Eli Lilly and company had released an important internal training document, called the Assay Guidance Manual, to the public and early on I made it a point to read that book “cover-to-cover”. Having that opportunity to learn some of the tribal knowledge from pharma through the AGM chapters meant a lot to me and I was really excited when the editor-in-chief, Dr. Sitta Sittampalam, who initiated that manual while working at Eli Lilly back in the 1990s asked me to join him as an editor. As a research scientist at NCATS, I collaborate with a number of scientists that do basic research to establish a translational focus. Having come from that environment so recently, I really understand some of the challenges that they face. Therefore, as an editor of the AGM, I try to do as much as possible to help make critical information available to the researchers who need it.
Paul, Would you please highlight some of your Malaria research?
My group has been studying malaria for a little over 20 years. Our primary interest is in elucidating drug resistance mechanisms and how dissecting drug resistance at a molecular level can assist development of “second tier” therapy that is effective against drug resistant strains or cells. We’ve studied drug resistant tumors, bacteria, and parasites, but the majority of the group is focused on malaria questions these days. We’ve always been a highly interdisciplinary group, with students and postdocs that are studying chemistry, molecular biology, biophysics and other disciplines as well coming in and out of the group on a regular basis. Antimalarial drug resistance is one of those topics that demands interdisciplinary perspective and since we are always learning new techniques and approaches we’ve relied heavily on generous collaborators to teach us what we need to know. All of this makes our lab a vibrant and pleasantly intense place to work.
One of our first projects in antimalarial drug resistance (back in the late ’90’s) started with collaborative work we did with the Tom Wellems laboratory at the NIH on identification of the PfCRT gene. Back in those days Tom’s group was in the “LPD” or Laboratory of Parasitic Diseases in good old Building 4 on the Bethesda campus. This was mid 1998 as I recall, and Tom’s lab was filled with a crop of terrifically smart postdocs and research associates (Michael Ferdig, Kirk Deitsch, David Fidock, Roland Cooper, Xinzhuan Su, Takashi Nomura, Bronwen Naude, as well as a number of others). My laboratory still collaborates with several folks from that old group, David and Xinzhuan are co – investigators on two of our grants, and Michael has published several papers with us in recent years. Those were truly exciting days, malaria research in this country was starting to gain additional momentum as problems became a bit more tractable and the NIH and other agencies and foundations began to pay more attention to the disease.
Tom had done a tremendously important experiment back in the early 1990’s when he crossed chloroquine sensitive (CQS) and chloroquine resistant (CQR) parasites and was able to clone 36 progeny. About 1/2 of these were found to be CQS, and 1/2 CQR, suggesting resistance to chloroquine and perhaps other quinoline antimalarials was “Mendellian” and controlled by inheritance of a single gene. As long as resistance is defined by an IC50 shift, this indeed turned out to be the case, as a paper we were privileged to co – author with Tom and his group back in 2000 proved. The gene that was described in that paper, “pfcrt” remains an active area of research in my group to this day.
The encoded PfCRT protein turns out to be vacuolar membrane protein that is intimately involved in vacuolar physiology. When PfCRT is mutated in certain ways, resulting in patterns of multiple amino acid substitutions, the protein is able to mediate electrochemically downhill transport of charged chloroquine from inside the vacuole (called the digestive vacuole or DV) to the cytosol. This is a key aspect of the CQR mechanism. When pfcrt was fully sequenced from different isolates in 1999, we only knew of two different resistance – conferring alleles (one found in SE Asian and African parasite isolates, named “Dd2” after the Dd2 laboratory strain cultured from one of those isolates, the other named “7G8” found primarily in S. American CQR parasites). Since then, dozens of additional PfCRTs have been discovered in additional isolates from around the globe. The widely accepted hypothesis is that these reflect different drug selection histories or variable drug selection pressure applied in different geographic regions. It underscores the important principle that malaria is a global disease with a high degree of regionally specific variability. Various drugs have variable effectiveness in different regions. As we learn more and more about the different “sub types” of P. falciparum malaria that are carrying different pfcrt alleles (as well as other mutations) we and other groups have been better able to more accurately model various drug resistant phenotypes and to screen for drugs and drug combinations that show increased potency vs those sub types.
Paul, Can you tell us about your collaborative work given your roles with Georgetown, the …NIH, Notre Dame, Case Western Reserve, Walter Reed Army Hospital, Johns Hopkins and Columbia just to name a few?
Currently we have two major projects. The first, which includes some collaborative work with Dave Fidock’s lab at Columbia, as well as Geoffrey Chang’s lab at UCSD, is focused on more detailed understanding of newer PfCRT isoforms that have been found to be expressed in isolates from around the globe. Both collaborations are vital, David’s lab is one of the world experts in creating mutant laboratory strains of P. falciparum and Geoffrey’s is one of the best at membrane protein structural analysis.
The second major project revolves around defining new potent antimalarial drug combinations. There we collaborate with the Craig Thomas group at NCATS / NIH, Xinzhuan Su’s group at NIAD / NIH and two laboratories at Johns Hopkins headed by David Sullivan and Theresa Shapiro. The five groups bring different, highly complementary expertise to the project, it’s a wonderful consortium to be able to work within.
Nathan, (#4) Can you describe for our audience the Assay Guidance Manual? How it is useful? How does having it as an online updated resource confer benefits versus as a 1-time printed work?
The assay guidance manual is a treasure chest of information about assay development, operations, and a variety of critical concepts that facilitate the preclinical drug discovery process. Currently, there are 39 chapters that span ten sections and nearly 1000 printed pages. This book combines the tribal knowledge and wisdom of more than 100 drug discovery scientists from the pharmaceutical industry and it was a very important training document within Eli Lilly and company and Sphinx Pharmaceuticals. The emphasis of the Assay Guidance Manual is on the development and validation of assays with biological and therapeutic relevance using cutting-edge technologies. We have found that the Assay Guidance Manual content appeals to a fairly diverse group, including early career scientists, late career professionals as a refresher and even (#5) folks in senior management who are interested in learning about the current trends in assay technologies and best practices.
Similar to many journal articles, the AGM chapters offer pubmed citations for the authors; however, unlike many other publication platforms, the AGM chapters are not “written in stone”. The AGM chapters are living documents that can be revised on a quarterly basis. This allows both the eBook and individual chapters to grow with advances in technologies and methodologies. Additionally the format supports the inclusion of best practices and guidelines from different perspectives and settings throughout the world. This is because new authors can contribute to an existing chapter. Many of the chapters include authors from industry, academics, and government. Individual chapters grow as new authors continue to develop them. The eBook is edited and chapters are reviewed by a diverse editorial staff of 23 members from industry, academic and government settings.
Paul, (#6) For Malaria in particular, what biological insights are key to having therapeutically relevant bioassays?
There are a number of biological insights that are quite relevant. Malarial parasites are unique organisms, their biology is quite fascinating and complex. They are intracellular parasites that infect both mosquitoes and their vertebrate host. Approximately 160 species of Plasmodia are found on the planet and they can infect all known vertebrates. Humans are infected by 5 species, with P. falciparum and P. vivax being the most important. Once within humans, malarial parasites invade liver cells and then red blood cells (RBCs). They also exist (briefly) as free blood forms called sporozoites (which are released during a mosquito blood meal) and as merozoites (released from the liver as large clusters of thousands of merozoites known as “merosomes”). So the first key point that requires detailed attention is that the microbe you are screening against exists in a multitude of very different, highly differentiated forms. If you want to screen against the RBC stages, your culture system will include fresh RBCs and matched human serum. If you want to screen vs the free blood form known as a gametocyte, you’ll need separate, highly specialized culturing systems to enrich for that form. And so on. These different culturing systems make screening for compounds effective against most or all of the human stages quite difficult; drugs active against all forms cannot be found via only one screen.
Nathan, (#7) Why did you include a Chapter in the Assay Guidance manual on informatics titled: “Development and Applications of the Bioassay Ontology (BAO) to Describe and Categorize High-Throughput Assays” (by Uma Vempati and Stephan Schurer)?
The major focus of the assay guidance manual is on methodologies and best practices to support assay development, high-throughput screening, and lead discovery. The gift of the Assay Guidance Manual from Eli Lilly and company between 2004-2005 was intended to benefit preclinical drug discovery initiatives worldwide. This time period was also the beginning of the NIH Molecular Libraries Program, which involved a number of centers located throughout the United States that increased public access to small-molecule science through high-throughput screening in order to advance translational research. Prior to the Molecular Libraries Program, access to high-throughput screening had been primarily limited to the pharmaceutical industry.
The Assay Guidance Manual was made available from the NIH chemical genomics center website to guide both work being done at the screening centers and public understanding of the resulting data. The PubChem database was created to allow public access to the very large datasets that were being generated by screening centers of the Molecular Libraries Program. This was the first time the public had access to data of this type, which included data from primary screens, confirmation screens and secondary assays, such as counter and orthogonal assays. At the time there was no easy way for the public to organize the diverse datasets to allow systematic querying. The Bioassay Ontology was developed to support public access and use of the chemical biology data from PubChem. This chapter was published in the Assay Guidance Manual, so that readers can understand what the ontology terminology is and how it is applied to data from high-throughput screening and how it can be used to examine information in the database.
Nathan, (#8) What should experimental researchers know about emerging informatics technologies to do their jobs better?
The power of applying informatics approaches to research questions is rapidly increasing as are experimental technologies and our overall understanding of biology. Researchers worldwide have a growing wealth of data comprising very diverse biological measurements. Publicly available informatics tools, including the Bioassay Ontology and the BioAssay Express allow researchers to utilize these large databases to develop and test new experimental hypotheses. Additionally, these tools can be used to facilitate multidisciplinary collaborations among biologists, chemists, engineers and bioinformaticians.
Paul, Both target- and phenotypic-based approaches to drug discovery offer advantages and disadvantages. How do you view and apply these different approaches in your own research?
We use both, often there isn’t a preformed notion as to which will be best, often it’s just what is available at the time. I suspect that as our understanding of the malarial parasite proteome continues to improve, we will see many more target – based approaches.
Paul, How do you take into account all the different relevant factors from epidemiology to resistance to malaria biology to screening assays?
That’s a very good question. I rely quite a bit on my research group to help me stay up to date on the literature. With a diverse interdisciplinary group that’s a bit easier than you might expect, each week we have journal club and data presentations where individuals in the group take turn presenting, and almost always that presentation includes a deep and critical evaluation of recent literature. Since interests across the group vary, we manage to stay reasonably up to date. Of course collaborators outside our group are a huge help in this as well. The malaria community has many generous people that are quite collegial about sharing information.
Paul, You were interested in the public malaria data in CDD Vault – how relevant and helpful are malaria data sets such as the MMV Malaria box, Johns Hopkins’s and NCAT’s FDA approved libraries, and GSK’s Tres Cantos anti-malarial set? How can we use our knowledge of previously screened compounds, resistance, and approved drugs to best focus our future antimalarial drug screening efforts?
All of these have been helpful, and to many groups across the planet. We have many attractive compounds that could conceivably be developed into better drugs. The situation is remarkably better today that it was just 10 years ago, largely because of the accessibility of the (#9) tools you mention. I think what needs to happen next is exemplified by work we are doing with Craig Thomas and his group at the NCATS. Even though most laboratories screen for antimalarial activity one drug at a time, in the field, monotherapy has largely been abandoned; we use drug combinations. Paradoxically as a community we don’t tend to screen for combinations, and there are differences of opinion in how to prioritize (#10). Obviously the combination needs to be potent and safe, my opinion is that it is also best if they show synergy, and the higher the synergy the better. So screening for this traits in the very large collection of possible drug combinations is a new challenge.
Nathan, Tell us about the quarterly usage and your Research Workshops?
After Eli Lilly and company released the AGM to the NIH between 2004-2005, several publication platforms were explored. Initially the entire document could be downloaded from the NIH chemical genomics center website. Also a wiki format was explored for a period of time, but the authors found the format difficult to work with. In 2012 the content was published as an eBook on the National Library of Medicine/National Center for Biotechnology Information bookshelf. There are two major advantages of the current publication platform. First, these eBook chapters have PubMed citations for the contributing authors, which is very important for both recruiting new authors as well as the overall visibility of the content. Secondly, this format allows the eBook to exist as a living document that grows with contributions from researchers worldwide. We update the eBook quarterly to keep the content current. In 2013 were able to begin tracking the number of times the AGM content is accessed. Over the past 3 years we have doubled our viewership from about 50,000 retrievals of the content quarterly in 2013 to about 100,000 per quarter in 2016.
My primary responsibility at NCATS is to collaborate with academic and government researchers to develop different types of assays suitable for high throughput screening. I was aware, not only from seeing the substantial growing popularity in the Assay Guidance Manual, but also from my interactions with collaborators, that there is a strong interest among many researchers in learning about assay development for high-throughput screening and lead discovery. An assay is really the heart of any drug discovery and development program up until a molecule (#11) reaches the clinic. The Assay Guidance Manual editors decided to establish a workshop that focuses on a variety of critical concepts from the manual. Many of the workshop instructors have 20-30 years of experience in the field of drug discovery. These workshops allow participants to really take advantage of the instructors tribal knowledge and practical experience of how to develop and validate assays. To date, we have held five workshops: the first one was at NCATS and it included tours and discussions of laboratory automation instrumentation. We held two workshops at the US Food and Drug Administration and one of them spanned two days. In October, we held a workshop at the (#12) Promega Corporation, following the International Chemical Biology Society Conference on Translational Chemical Biology in Madison. Last year we held a workshop with the annual international 2016 Society for Laboratory Automation and Screening (SLAS) conference and due to the success of the event, we will be holding another workshop at the 2017 conference in Washington DC at SLAS2017 on Saturday February 4, 2017.
Nathan, What topics have been added recently to the Assay Guidance Manual and what topics would you like to see added next?
We have recently introduced entirely new sections to the Assay Guidance Manual, including a section on Assay Artifacts and Interferences which already contains 3 chapters by leaders in the field and several more chapters are in development. Also, we have just added a section on pharmacokinetics and drug metabolism with a new chapter by Dr. TC Chung and colleagues. Within the In Vitro Cell Based Assays section, we recently published a chapter on the application of the cellular thermal shift assay or CETSA to high-throughput screening by Dr. Thomas Lundbäck and colleagues. The CETSA methodology provides a powerful and unprecedented approach to validate target engagement within the context of a living cell. Another exciting recent addition is a chapter on in vitro 3D spheroids and microtissues by Dr. Jens Kelm and colleagues, which is a rapidly emerging area of interest in assay development.
At the moment there are another 26 chapters in different stages of development that focus on a diversity of topics, from guidelines for reviewers of HTS grants to medicinal chemistry for biologists. In terms of the topics we would like to add, there is a need for new chapters describing assay development using stem cells, phenotypic screening and 3D cell constructs, biophysical methodologies, medicinal chemistry, pharmacokinetics, toxicity and safety studies, drug metabolism, and biomarkers.
Nathan, Walk us through a few highlights from other sections of the detailed Assay Guidance manual…and how they might be helpful for the global drug discovery community in both academia and industry?
(#14) The first chapter of the Assay Guidance Manual provides guidelines for academic researchers and start-up companies to assist in planning for different types of drug discovery projects from the initial target validation all the way up to the point of clinical trials. The information includes detailed timelines, estimated associated costs, key decision points, definitions for vocabulary and potential sources of funding. Following that chapter are 24 chapters on biochemical, cell-based and in vivo assay guidelines. (#15) Our In Vitro Biochemical Assays sections contains 9 chapters that cover a number of important topics. There are many chapters about enzymes covering important topics such as validation of identity and enzymatic purity, basics of enzymatic assays for high-throughput screening and mechanism of action assays. There are chapters for specific types of enzymes and also chapters that cover other types of biochemical assays, such as protein-protein interactions (#16), receptor binding assays and immunoassay methods.
The In Vitro Cell Based Assays is our largest section with 14 chapters, including our most popular chapter called “Cell Viability Assays” by Dr. Terry Riss and colleagues. That chapter was recently revised to include a section about a novel real-time assay to monitor live cells for days in culture that can also be multiplexed with a variety of other assay chemistries. We also have a chapter about cell line authentication by Dr. Yvonne Reid of ATCC and colleagues. There are a number of chapters about image-based high content assays, chapters about ion channels, cell-based RNAi assay development and cardiomyocyte impedance assays. These chapters provide readers with suggestions for robust assay methods and include tips for assay optimization, trouble-shooting and data analysis. We have a rapidly growing section devoted to assay artifacts and interferences and a section with 5 chapters about assay validation, operations and quality control. We also have an Assay Technology and Instrumentation sections featuring chapters that describe some of the specialized equipment utilized for high-throughput screening. For example, there are often challenges associated with adaptation of an assay from the benchtop to a fully automated system (#17). Successful adaptation requires an understanding the instrumentation commonly utilized in high-throughput screening, which are described in the Assay Guidance Manual. We have a new section on pharmacokinetics and drug metabolism, which will be growing with future contributions. The last chapter is a glossary with terms that can be found throughout the book.
Paul, You are well known for applying multidisciplinary approaches to research problems and have developed assays and methodologies to advance antimalarial drug discovery. Are there malaria targets or aspects of malaria that you think hold promise for therapeutic development which remain challenging due to technological limitations or a lack of appropriate assays?
(#18) Sure, there are many of them. Simplistically, we still don’t even know what over 1/2 of the encoded proteins in the P. falciparum genome do. They are annotated as “unknown function” in part because there are very few (if any) orthologues for many of the genes. This can obviously make target identification very difficult, and if you identify an “unknown function” protein as a target, then developing assays involving that protein is very difficult. (#19) We and many others are struggling with this right now in trying to understand what the “kelch 13” protein is doing in conferring an artemisinin delayed clearance phenotype to malarial parasites.
Paul, You have studied drug resistance in both cancer and malaria. Can you highlight some of the similarities and (#20) differences that drive resistance in these cells? Also, has investigating drug resistance in these very different types of cells raised interesting research questions that you are following up on?
I think a simple concept that is applicable to both is that we now know that drug resistance can be either “intrinsic” (meaning the tumor or the strain of malaria is naturally less susceptible to a given drug prior to drug exposure), or “extrinsic” meaning it is either induced or selected for by the drug or some other stress. Some research shows that the mechanisms for these might overlap in certain examples, but more often they are probably distinct. Another shared feature that I think is very important, but that has been somewhat neglected, is that there are typically at least two layers of resistance. What I mean by that is that most antimalarial and anticancer drugs are both cytostatic (meaning they slow the rate of cell growth) and cytocidal (meaning they kill the tumor cell or parasite cell). Often the ‘static and ‘cidal mechanisms of action are different, for example, vinca alkaloid drugs slow tumor cell growth by interacting with tubulin, but often kill by inducing apoptosis. In these examples, if the mechanism of drug action has two layers, then the mechanism of resistance to the drug can have two layers. Often when we are studying a single example and get an answer for how cytostatic resistance works, we stop looking. Which leaves the problem 1/2 unsolved in my mind.
Paul, Currently there is intense activity world-wide to develop more physiologically relevant assays that incorporate multiple cell types and microtissues. Many researchers are finding that experimental results can be dramatically different when comparing traditional methods for cell-based assays to more recent 3D systems. Dr. Michael Gottesman of the NCI for instance has reported measuring very different expressions of genes that contribute to drug resistance in cancer cells when comparing results from monolayer cultures against more advanced 3D models. Have you had similar experiences and are you also exploring new methodologies to advance your own cell-based assays?
I guess the parallel for us would be in trying to compare cell based results vs results from animal models of malaria. The field would very definitely benefit greatly from improved animal models.
Based on the conversation, how might each of your areas of expertise and networks help each other? How might the lessons from Paul Roepe’s domain expertise in relevant Malaria assays be relevant with lessons for the Assay Guidance Manual community? Conversely, what lessons from the Assay Guidance Manual (and/or other work done at NIH) be relevant to the Malaria research community? What lessons might be transferable?
Paul is working at the bleeding edge of malaria research and his current work with combination screening is an incredibly important and rapidly developing area for assay technology, instrumentation and data analysis. This type of work requires specialized instrumentation assay considerations, workflow and analytical methods. We do have a chapter in development to provide guidance for combination screening initiatives. Myself and the other editors of the assay guidance manual are really committed to supporting researchers like Paul with information that will help them maximize the impact of their studies and resources. We certainly want to be aware of any needs among the research community that we can address to benefit researchers worldwide.
How can researchers benefit from modern web-based technologies to accelerate research? Both for sharing and receiving vital information? Where do you see the trends going in the future?
The modern web-based technologies are really driving new collaborations by making it possible for researchers with shared interests, who might be quite separated geographically, to work very closely together in real time. Even among individuals located within my own center many of my meetings are web-based and also include folks located off site. The clear benefit is that research teams can be assembled and functional without the requirement of establishing a particular location. Also these teams can benefit from the expertise and resources available from multiple locations.
How can biologists help chemists – and vice versa?
From my perspective, biologists are often more aware of the strengths and limitations of different types of assays that directly inform the chemistry. For instance, the biologist will know assay performance metrics, such as the minimum significance ratio, which defines the ability of a screening assay to differentiate and rank order compounds as well as the assay robustness and replicability. The biologist is also well aware of potential mechanisms for assay artifacts, and limitations in the assay that deviate from physiological relevance, such as a purified protein that is truncated or missing critical post-translational modifications. Therefore, biologists can be very helpful to chemists by communicating many important details about the assay which guides the chemistry. On the other hand biologists often have a limited understanding about the properties that make one compound more attractive to work on than another. For instance due to drug like properties, liabilities or synthetic feasibility. At the moment there is an assay guidance manual chapter in development on medicinal chemistry for biologists.
How has the interdisciplinary, collaborative aspects of science changed since when you first started your careers? What advice would you have for young scientists starting their careers today?
From my perspective over the course of my career so far, I have seen increasing collaborations among researchers with diverse backgrounds, such as physicists and engineers working side by side with biologists. Also, I have seen that the pharmaceutical industry is increasingly establishing collaborations with academic and government laboratories.
Kellan:Thank You all for your questions–We’ll be posting future webinars on the CDD Website.
Frank:We want to thank Nathan and Paul for their time and sharing their experiences with us today. Join us (#21-23) early in 2017 for our continued Webinar series… Good day everyone.
Due to sound issues with Paul’s connection, we cannot feature the recording, however it is available.
This blog is authored by members of the CDD Vault community. CDD Vault is a hosted drug discovery informatics platform that securely manages both private and external biological and chemical data. It provides core functionality including chemical registration, structure activity relationship, chemical inventory, and electronic lab notebook capabilities.
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