June 12, 2012
CDD Spotlight Highlights
"When you see that activity in a mouse model with the compound that you designed and made and ushered through those early stages, that's really, really exciting...We use CDD Vault all the time for programs where we are evolving structure activity relationships, understanding how a small molecule modulates the target. We are able to track those changes in both graphical and numerical ways seeing how structure influences inhibition of a target. That is just incredibly valuable to us, together with the ability to share the information amongst many different collaborators whom I'm really privileged to have. It is extremely important to exchange data in a seamless fashion. And there is the immense amount of public data that's been archived on CDD Vault."
Joel Freundlich spent 8 years in the pharmaceutical industry after earning his Ph.D. in Organic Chemistry from MIT, before moving into academia. He is currently Associate Professor (Pharmacology, Physiology and Neuroscience - NJMS) at Rutgers University, leading the Freundlich Lab
Interviewed by Barry Bunin, PhD, CEO, Collaborative Drug Discovery, Inc.
Listen to the Full Audio
[audio src="/wp-content/uploads/2012/03/freundlich.mp3"]
Edited Interview Transcript
Barry Bunin
I thought I would start by just having you introduce yourself and talk about your past research and future research.
Joel Freundlich
I’m Joel Freundlich, an Assistant Professor at UMDNJ - New Jersey Medical School in the Department of Pharmacology & Physiology, the Department of Medicine, and the Center for Emerging and Reemerging Pathogens.
I spent 10 years in the biotech pharmaceutical industry. After my PhD at MIT I was indoctrinated into the world of medicinal chemistry from an industrial perspective. After probably about eight years, I was introduced to the field of malaria and found my way back to academics at Texas A&M, the Department of Biochemistry and Biophysics, as a senior scientist. I really got involved using chemical tools to probe the essential biology of the parasite for malaria- Plasmodium falciparum, and then also the pathogen pertinent to tuberculosis infection- Mycobacterium tuberculosis. That was really the beginning of my academic work, as far as trying to leverage chemical methods to understand how to validate targets pharmacologically within those pathogens for therapeutic intervention, and also just to increase our basic understanding of the biology of these pathogens.
Barry Bunin
And what are the end goals of your current research, as well as some of the means to achieving those in the short-and long-term?
Joel Freundlich
We seek to study how the pathogen adjusts to life within the host and then, in turn, see how the host adapts to the infection. The end goals are really to understand these adaptations at the level of the target, and to pharmacologically validate that target.
For example, one could try to investigate whether a target is essential for infection, especially at the level of in-vivo model infection, for example a mouse model. Validating these targets is very important, and then supplying molecules that will be drug leads in the pharmaceutical definition. This really sets the stage for working together with a pharmaceutical company, with them putting a significant amount of medicinal chemistry effort into optimizing molecules that we've created, and try to move forward in a true drug discovery effort on an industrial scale.
Barry Bunin
So why and how do you use CDD?
Joel Freundlich
Our relationship with CDD has gone back at least five years I would say. When you first emailed me, Barry, many years ago just to take a look at the software, I was really thrilled with it. It is just an excellent way of keeping track of structure activity data in quite a facile way. We use CDD all the time for programs where we are evolving structure activity relationships, understanding how a small molecule modulates the target. We are able to track those changes in both graphical and numerical ways seeing how structure influences inhibition of a target. That is just incredibly valuable to us, together with the ability to share the information amongst many different collaborators whom I'm really privileged to have. It is extremely important to exchange data in a seamless fashion. And there is the immense amount of public data that's been archived on CDD. It is very valuable to have data sets like SRIs screening against TB in a whole cell fashion, to be able to just look through those structures to query a substructure and to see how many hits you get, see what those molecules look like. I know that CDD are huge proponents of data sharing, and it's very valuable for the community. It’s going to be critical for the neglected disease area to share data as efficiently as possible if we want to leverage what everyone's done to move forward towards cures for these diseases.
Barry Bunin
You mentioned collaboration. How do you work collaboratively both internally, within the groups you've been part of, and externally, with other groups? Just talk about some of your collaborations, what things have worked and what you could see perhaps working better in the future?
Joel Freundlich
I absolutely think it's very important to have a collaboration amongst equals where everyone is aware of the valuable contribution that each team member is making. I really have to commend everyone in the TB and malaria fields because I think they have really learned the importance of collaborating, and how the end product is reliant on contributions from everyone on the team. You can't do it all by yourself with these medical problems of huge importance, and collaboration just moves things forward at a much more rapid pace.
Barry Bunin
You’ve worked and published in a number of fields, and you alluded to this a little bit earlier, but just wanted to go in a little more depth in terms of how CDD could be useful or is useful for TB research, but then also for another area such as drug repurposing/repositioning, just to contrast the two different areas that you’re expert it.
Joel Freundlich
CDD provides an immensely valuable resource of structure activity relationships that other people have contributed: has anyone made this molecule and tested it against TB, is just so important to know. You can search the literature and other tools that we have these days are of increasing power than they were ten years ago or 20 years ago, but CDD has been quite comprehensive in the TB field in terms of archiving data, and so it’s very valuable.
In terms of repurposing, which Sean Ekins and I have published on before, and Sean and you have certainly published extensively in this area. CDD has much of that data archived and one just has to draw the structure and press a button and it's really at your fingertips. At this stage, we don't want to reinvent the wheel. I think that we realize that small molecules are tools. They have value onto themselves, but I think they are most valuable in terms of this chemical probes, and hopefully the seeds of eventual therapeutics. So it's really important to have access to known drugs, approved drugs, and the assay data to see if people have screened them against the disease of interest, and see what the actual data looks like. It’s really important both at the level of just seeing if there's really good activity, so even an approved drug could somehow be repurposed right away as an anti-malarial that'd be great. Otherwise, they still have value as chemical probes. That moves away from the definition by Collins and Workman I believe, where they define a chemical probe as something that's very, very specific in terms of biological activity. I would suggest possibly broadening that definition, as long as the activity is not rampantly promiscuous, hitting many targets, but I think the repurposing can also allow one access to very valuable chemical probes.
Barry Bunin
Can you talk about someone else’s research that you thought was interesting or remarkable and worth sharing.
Joel Freundlich
A paper that comes to mind recently is from Eric Rubin, Chris Sassetti, Kyu Rhee and Dirk Schnappinger and others (Wei JR, Krishnamoorthy V, Murphy K, Kim JH, Schnappinger D, Alber T, Sassetti CM, Rhee KY, Rubin EJ. Depletion of antibiotic targets has widely varying effects on growth. Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4176-81.) That’s just an excellent paper, because it looked at the very interesting issue of target vulnerability. They looked at the extent to which one has to knock down the protein level in order to see a growth defect in a whole cell assay. It builds on work from Eric Rubin's lab along with Chris Sassetti (PMID: 11606763, PMID: 12657046, PMID: 14569030) and work from Bill Bishai and Gyanu Lamichhane,(PMID: 12775759, PMID: 15784600) where they look at transposon site mutagenesis data to establish what genes in TB are essential under a given set of in-vitro or in-vivo growth conditions. The work by Eric Rubin and others is intriguing and thought provoking in terms of what targets appear to be most vulnerable, and allowing us to prioritize our efforts in the area of TB drug discovery. And I think it is a fundamentally interesting issue in terms of what factors contributed to this vulnerability, so I applaud that publication.
Barry Bunin
Can you talk about one interesting result or experience that you had during your ten years in the industry that was enlightening.
Joel Freundlich
I think industry is very good at making tough decisions at carving out a critical path that's as time efficient, as cost efficient as possible. They ask questions about what milestones are critical, what activities are critical in order to drive a new therapeutic, which is very important, and is something that academics tend to forget, holding onto pet projects too long. One could also argue the flipside that holding onto things a little bit longer sometimes pays off, but industry has to make go-no-go decisions in order to be as time and cost effective as possible.
Barry Bunin
You alluded to the flipside, what's been one interesting personal experiences or an “ah-ha” moment in your academic career where a result was particularly interesting or exciting for you?
Joel Freundlich
I’ll try not to divulge too much that's pertinent to publications, but I think when you see in-vivo activity of a compound in an animal model, I think that's really, very exciting. There are always very good arguments that one can make in terms of the TB field how well the mouse model of infection mirrors the actual human infection by Mycobacterium tuberculosis. At the same time there is a very good correlation between compounds that show efficacy in mouse models and in humans. I think it's a first step down that path towards really having an effect in a field and showing in-vivo activity. When you see that activity in a mouse model with the compound that you designed and made and ushered through those early stages, that's really, really exciting.
Barry Bunin
So that's a good note to end it on. So thanks for your time, Joel, and a wonderful CDD Spotlight.
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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