The Bioinformatics CRO Podcast

Transcript of Episode 73: Nataraj Pagadala

Disclaimer: Transcripts are automated and may contain errors.

Grant Belgard: Welcome to The Bioinformatics CRO Podcast, where we talk to scientists, founders, and leaders at the intersection of computation and biology. I’m your host, Grant Belgard. I’m joined today by Dr. Nataraj Pagadala, founder, president, and CEO of LigronBio. LigronBio is a biotech company focused on molecular glue therapeutics, small molecules that co-opt the cell’s own protein degradation machinery to go after proteins that have traditionally been considered undruggable. The company is applying computational chemistry, bioinformatics, and AI-driven platforms like its tri-matrix analyzer to design these glues and target neurodegenerative diseases and other serious conditions where new therapies are badly needed.

Grant Belgard: Nataraj has more than two decades of experience in computational drug discovery, spanning academia and industry from early work in biochemistry and bioinformatics through postdoctoral and research roles, modeling protein structures and aggregates, to senior positions in biotech and now founding his own company. Today, we’ll talk about what he’s working on now at LigronBio, how his career path led him into molecular glues and company building, and the advice he has for students, trainees, and scientists who are now thinking about careers in computational drug discovery, or even starting their own companies. Nataraj, thanks for joining us. Great to have you on the show.

Nataraj Pagadala: Thank you very much, Grant. Thanks a lot for, you know, giving me the great opportunity for the molecular glue audience and also for the targeted protein degradation companies. This is Nataraj Pagadala, founder and CEO of LigronBio, and LigronBio is incorporated in 2023, working on targeted protein degradation space, developing molecular glues for all undruggable targets in oncology side and also in neurodegenerative diseases, mainly focused on Alzheimer’s, and later on it will be extended to Parkinson’s and also ALS therapeutics. So, primarily, we are developing the platform called as the AI TriMatrix Analyzer Platform to rationalize and discover molecular glues for the specific undruggable targets in Alzheimer’s space, and also this is linked with the diagnostic kit, which is called as an L-tag assay.

Nataraj Pagadala: This particular L-tag assay will help in the functional studies of these molecular glues to take it further for preclinical studies and also for clinical trials. So, this is a powerful engine linked with generative AI that will help in discovery of these molecular glues within 36 months.

Grant Belgard: So, for members of the audience who have never heard of molecular glues, what are they?

Nataraj Pagadala: Molecular glues are the small molecules, which is very, all the medicinal chemistry properties are similar to traditional drug molecules, except that the difference between general traditional molecules and molecular glues are these molecules, they do the protein degradation compared to the traditional drug molecules where they inhibit the proteins in the biological system. So, for the undruggable targets, basically, there is no binding pockets where actually these undruggable targets help in the progression of the disease, even though there are the proteins which can be inhibited by the traditional drug molecules. So, that is the reason why these molecular glues are designed especially for the undruggable targets for protein degradation.

Grant Belgard: When you explain your company’s mission to someone with biology background, what do you emphasize first, the disease areas, the modality, or the technology platform?

Nataraj Pagadala: So, basically, our mission is basically to design the molecular glues for any of the disease-specific proteins, which is undruggable mainly. So, at the same time, our mission is to do the targeted protein degradation for the diseases and also help in reduction of the proteins in the biological system and also the disease progression. So, our vision is very broad to develop a molecular glues for all the undruggable targets, you know, and to save the future generations from Alzheimer’s is our very big mission.

Grant Belgard: Are there any currently approved molecular glues?

Nataraj Pagadala: Yes, yeah. So, there is a couple of approved molecular glues. The two are, one is palmolidamide and also one is lenidamide, which is in the market as a revlimid for multiple myeloma. So, and also, it is a very big market for this particular molecular glues for multiple myeloma disease.

Grant Belgard: So, what convinced you that there is space for a new company in this area?

Nataraj Pagadala: So, basically, if you see from the last 10 to 15 years, many companies are developing molecular glues in the targeted protein degradation, but unfortunately, all these companies, they are literally, were not completely successful in developing molecular glues for any disease-specific or also the target-specific because of a lack of a serendipity. So, this is the reason why LigronBio came into picture. We are developing because of, you know, serendipity reasons, you know, to rationalizing the molecular glues and discovery of molecular glues is a very difficult task. So, we are developing right from the scratch. This is the primary reason why we are developing a TriMatrix Analyzer platform where actually this particular platform rationalizes the molecular glues and, you know, for a specific target using a generative AI that will help in discovery one thing.

Nataraj Pagadala: And also, at the same time, this particular platform also, you know, finds out all the off-target interactions, you know, that way we can eliminate all the serendipity problems within the biological system to develop a molecular glue for a specific target without any off-target interactions. That is the reason why LigronBio is a novel compared to all the existing platforms worldwide in terms of, you know, data integration with the AI and also high selectivity and specificity.

Grant Belgard: Neurodegeneration is notoriously difficult. What aspects of those diseases make them feel particularly well-suited for a molecular glue approach?

Nataraj Pagadala: Basically, if you see in the biological system with the neurodegenerative diseases like Alzheimer’s, right? So, that’s what I’m saying that, you know, there are many undruggable targets in the biological system that will help in the progression of the disease, not only in oncology side, but in also the neurodegen, neurological space in the neurodegeneration. So, these, as long as these undruggable targets exist in the biological system, it is very difficult for, you know, to inhibit the progression of Alzheimer’s or Parkinson’s and ALS. So, this is where actually, unfortunately, the targeted protein degradation space is not introduced into this neurological space and people are not successful as of now. So, this is where actually we need to develop these molecular glues and, you know, eliminate these toxic proteins which are undruggable from the biological system.

Nataraj Pagadala: That way, we can slow down the disease progression and, you know, restore the memory function and then also reduce the cognitive decline. So, this is where importance of molecular glues comes into picture with respect to neurodegenerative diseases.

Grant Belgard: How do you balance going deep on a few carefully chosen targets versus exploring widely across many possible targets with your platform?

Nataraj Pagadala: So, basically, this particular platform designs the molecular glues for any specific target. So, even though there is no three-dimensional structures of the protein done by crystallography or by any other method. So, this particular platform designs the molecular glue just by the amino acid. So, basically, if you see the undruggable targets, then there is a motif called, let’s say, degron. So, this degron is a six to seven amino acids or maximum 10 amino acids. So, based on that, this particular platform designs the molecular glue based on the amino acid. So, it is even the layman who doesn’t know how to design the molecular glues, this particular platform gives an opportunity just by typing, inputting the amino acid, amino, just an amino acid or a peptide sequence, it will develop a molecular glue.

Nataraj Pagadala: That’s where this particular platform is completely different from all the existing platforms worldwide.

Grant Belgard: What kinds of collaborations or partnerships are most important for a company like yours at this stage?

Nataraj Pagadala: So, at this stage, particularly because, you know, the experiments of targeted protein degradation is different than the traditional way. So, that is the reason why we need partnerships, you know, who are well-versed with the targeted protein degradation space. So, this is where, actually, we need the partners like BMS who is working on targeted protein degradation or also C4 Therapeutics or Chimera Therapeutics. You know, these companies are developing or working on a protein degradation, but unfortunately, they are not working especially on molecular glues, but they are working on other modality called as a protag. But, you know, there are some companies who are working on especially on molecular glues, but, you know, they were not successful as of now.

Nataraj Pagadala: So, we can help those kind of companies, you know, we can help, we can also partner with those companies to design the molecular glues with this particular platform and also help them to, you know, for the targeted protein degradation with the molecular glues with our platform. That’s where, you know, we can partner with those companies and we also, we can help those companies for developing a molecular glues.

Grant Belgard: When you think a few years ahead, what would success look like for LigronBio?

Nataraj Pagadala: Earlier, a few years ahead, right? You know, that time, actually, to be honest, funding is much flexible compared to this particular time where, you know, funding is a very bit hard. So, because of not successful by many of the companies. So, otherwise, you know, by today, LigronBio might have developed the molecular glues for the Alzheimer’s therapy. And by today, we might have at least reached the patients, you know, clinical trials for Alzheimer’s therapy and also might reach the patients.

Grant Belgard: And is the vision to accomplish that through partnerships or are you planning on sponsoring trials as Ligron?

Nataraj Pagadala: Yeah, actually, we are also trying to do from our side, our own clinical trials. At the same time, we are also looking for the big partners. You know, once we complete the initial phase of studies, once we file the IND, then we are also looking for the big partners to step in and also do the clinical trials, you know, as a joint collaboration with LigronBio.

Grant Belgard: What do you see as the main advantages and disadvantages of molecular glues compared to more traditional small molecule approaches?

Nataraj Pagadala: The most important advantage of molecular glues is, you know, because this is an event-driven mechanism, the effectivity and also the degradation therapy is more effective for any disease compared to the inhibition. That is a major difference between the molecular glues and also the traditional inhibitors because the traditional inhibitors are an occupancy-driven mechanism. So, as long as you take the drug molecule, then the effect will be more on the disease state. But when in the molecular glues, even though the molecular, the drug will be eliminated from the biological system, then still the effect will be more. So, that is the reason why, if you see the efficacy is also very high when compared to traditional molecules, and the effect will be 100 times more than the traditional drug molecule.

Nataraj Pagadala: So, that is the reason why, and not only that, basically, the molecular glues are treat undruggable targets, which is notoriously undruggable in the biological system and helps the disease progression. As long as these, as I said, you know, earlier that these proteins are not eliminated from the biological system, the disease progression will still be there. That is the reason why we cannot stop oncology, we cannot, cancer progression, and also neurodegeneration. So, there actually, traditional methods cannot deal with those undruggable targets. Only molecular glues can help in that particular situation and, you know, help in the inhibition of disease progression.

Grant Belgard: What makes designing molecular glues hard, scientifically or computationally?

Nataraj Pagadala: Basically, I see, basically, as I said, you know, the molecular glues, they influence the target protein based on a simple motif, which is called as a degron. So, degron is always, you know, as I said, you know, maximum of 10 amino acids, right? So, this is not a catalytic site. This is a catalytic site for our traditional drug molecules is different than, you know, influencing the drug molecule based on this particular glue, which is a solvent exposed. So, you know, to formation of ternary complex is very, very difficult with respect to molecular glues. So, this is where the difficulty comes in, one thing, because as I said, you know, the degron is only 10 amino acids or maximum of 6 amino acids. So, there will be serendipity of the molecular glues because, you know, most of the kinases, you know, most of the kinases contains this kind of a degron where, you know, 6 to 7 amino acids.

Nataraj Pagadala: That is the reason why there is a high chances of off-target interactions with the molecular glues. That’s where we need to eliminate those molecular glues. And the AA TriMatrix Analyzer platform is the one that, you know, eliminates all these off-target interactions and gives them highly specific molecules for the time, you know, that shows a target protein degradation.

Grant Belgard: How do you think about modeling ternary complexes and cooperativity when you’re working with molecular glues?

Nataraj Pagadala: So, modeling, basically, as I said, you know, we are training a very big database of ternary complexes right from the literature and also from our own in-house experimental studies. And we are also, you know, mapping the proteome in the biological system for all the undruggable targets, you know. So, that will help us in, you know, to see that using a generate AI, artificial intelligence, you know, large language models, that will help us, you know, to see that, you know, how the molecular glues is especially, you know, seeing the off-target interactions. Once we eliminate that off-target interactions, it is easy for designing of molecular glues for a specific target. So, this is where actually that we are building the TriMatrix Analyzer platform.

Nataraj Pagadala: And also, because, you know, most of the targets doesn’t have a three-dimensional structure, this is where another advantage of this platform is that even though there is no three-dimensional structure, still we can develop a molecular glue for the particular target, you know, just based on amino acid as an input. So, this is where the advantage of this one, and also the difficulty that I said, you know, in most of the companies, they don’t have a three-dimensional structure, you know, for most of the targets, you know, unless there is no three-dimensional structure, there is no molecular glue. But a TriMatrix Analyzer platform can do this. And at the same time, most of the companies, to find out a ternary complex formation, they are using a diagnostic kits. Those diagnostic kits is based on the fluorescence.

Nataraj Pagadala: They only give indication about, you know, whether the ternary complex is formed or not. But when that is taken into experimental site, then it is not replicated. The diagnostic kit is not replicated. The results of the diagnostic kit is not replicated in the biological system in most of the cases. But we are developing a diagnostic kit in, which is called as an LTG assay, which gives information about, you know, how the ternary complex is formed, which is like an alternative to x-ray crystallography. That’s where we can clearly see that how the ternary complex is formed. So, this is where the difficulty from all the big companies are facing as of now. And that’s what we want to make it easier for all these companies, with our TriMatrix Analyzer platform, or also the diagnostic kit.

Grant Belgard: How do you decide which parts of the problem to treat with more traditional physics-based structural biology approaches versus more data-driven AI-ML approaches?

Nataraj Pagadala: So, basically, in the physics-based approaches, you know, most of these approaches are for traditional therapy for all the proteins which have a three-dimensional structure of the protein, right? You know, on the catalytic side, you know, there it is easy for the physics-based approaches, you know, for designing of the drug molecules. But data-driven approaches, this where actually, where we don’t have a proper [trim?] structures of the protein, this is where actually the data-driven approaches comes into picture. Now, just like, as I said, you know, for all the undruggable targets where we need lots of data, and lots of data to develop one molecular glue for a specific target.

Nataraj Pagadala: This is where AI and also machine learning and artificial intelligence comes into picture compared to, even though, basically, artificial intelligence and machine learning is also useful for traditional therapy, but especially because that even though artificial intelligence and machine learning is not needed, still we can develop a drug molecule for the proteins which have three-dimensional structures of the protein and also the catalytic pockets. But without the data-driven approaches and without AI and ML, it is very, very difficult to design molecular glue for undruggable targets.

Grant Belgard: How important is experimental feedback for your models and what does that loop look like in practice?

Nataraj Pagadala: Basically, the experimental studies is very important because, you know, the important thing is, you know, very, very rare that we see the targeted protein degradation effectively by molecular glue in the beginning. So, the experimental side is very, very important. I know because, you know, there are many factors that we need to find out in the area of targeted protein degradation, especially with the molecular glues, because, you know, the protag development is completely different. So, it is easy to find out the targeted protein degradation with the protags. But molecular glues is a small molecule and they influence the target protein through small motif. Sometimes, you know, we don’t know how the degradation is happening, you know, how the degradation is happening, whether the territory complex is formed. You know, this is a very complex system through molecular glues.

Nataraj Pagadala: That is the reason why the experimental data, not only that, you know, it’s like, you know, if you check, you know, thousands of, hundreds of molecular glues, sometimes, you know, we end up with no molecular glue showing a targeted protein degradation. So, that is where experimental data, one experimental data, and one targeted protein degradation will give a clue for many, many stages of a molecular glue development in the biological system.

Grant Belgard: Where do you see the biggest gaps right now in this space? If you could choose one particular type of data to just have a lot more of, or better data of, what would that look like?

Nataraj Pagadala: So, basically, I see the main gap here is, especially in the molecular glue is, you know, we don’t have a ternary complexes. So, that is where actually we cannot design a molecular glues, the ternary complexes, not only, and also from x-ray crystallography, especially from the x-ray crystallography, actually, how the ternary complexes formed, except, you know, five or six cases. Not only that, you know, because when these undruggable targets, you know, the ternary complexes formed, it’s a larger, you know, it’s a very big complex. It’s very difficult sometimes to create a three-dimensional structures of the proteins through the x-ray crystallography because of its complexity in nature. So, this is where actually the difficulty is coming from in the area of molecular glues.

Nataraj Pagadala: That’s where we need to do some computational studies in the beginning with enormous, generate enormous amount of data, what the ternary complexes, you know, mapping of all the ternary complexes. That’s where we get some clues to do the experimental studies. If it is replicated, then we can say that, you know, yeah, this is what is happening from my computational studies, and this is also replicated in experimental studies. Then from that, you know, generate more, you know, molecular glues for other targets, you know, more data-driven through AI and ML.

Grant Belgard: So, to talk about your career, looking back, what were the big inflection points that shaped your career in computational drug discovery?

Nataraj Pagadala: Basically, I did my PhD in computational chemistry in 2007. And after that, you know, I did four years of postdoc in the University of Alberta and one year of postdoc in Belgium in KU Leuven University. So, I have lots of my career, you know, 25 years of experience. But, you know, all my career, I worked on a traditional way, you know, developing a drug molecules for all the proteins, for all the proteins which has the binding pockets, you know, have a very great traction record of computational drug discovery from the last 25 years, you know, published for international publications. And also, I was also rated as one of the eminent scientists in computational chemistry by Carnegie Mellon University. So, you know, but unfortunately, I never worked on this targeted protein degradation earlier, before I started my career in [biotherics], you know.

Nataraj Pagadala: There, my journey of a targeted protein degradation has changed, actually. Yeah. So, from there, you know, after going in-depth analysis, you know, then I realized that, you know, this is a, it’s not a simple thing, you know. I need to, I need to show to the world that, you know, with all my experience that, you know, how can we design the molecular glues? How can we not only molecular glues, you know, how can, I know, targeted protein degradation can be done easily? That is the reason why I started this particular career. That’s where the, I know, the inflection point has come in my career to show to the world that, you know, how can we do this? Not only that, with the doing of this, now, how can we, you know, reduce the progression of the Alzheimer’s or Parkinson’s and also ALS and also major this, this devastating diseases, you know.

Nataraj Pagadala: With this technology, we can definitely protect the future generations because we know that COVID-19 has, you know, pandemic has created, you know, havoc in entire world, right? You know, half of the world was got wiped off. So, that is the reason why I changed my career that I want to do something to this, you know, in the disease therapy and I want to show something to this, you know, how can we, you know, stop the diseases or also we can, we can inhibit the disease progression and, you know, protect the future generations for, for these devastating diseases.

Grant Belgard: What gave you the confidence to start your own company doing this?

Nataraj Pagadala: So, basically, my experience, you know, from the last 25 years, as I said, you know, I have a great track record of, you know, computational drug discovery and also because, you know, as I said, you know, I, I did a full five years of postdoc in a PhD and publications, you know, my, as from Carnegie Mellon University, I was also rated as an eminent scientist. So, based on my career, my track record and my way of doing a drug discovery, so it’s completely, a little bit different, you know, compared to other people in terms of thinking, in terms of implementation. That gives me confidence that, you know, definitely my approach will help definitely for these diseases to, for the disease progression, inhibit the disease progression.

Nataraj Pagadala: So, that is the reason why with all my computational chemistry, because not only that, you know, my other confidence is because I’m a, I’m a biochemistry background. Mainly, my, my background is biochemistry with a genetics, you know, with a PhD genetics department. And also, I’m well-versed with molecular biology and all the biology aspects. So, that’s where actually, I can easily connect my biochemistry experience with a computational chemistry experience, with a drug discovery experience, and also experience in biophysics. So, with all these subjects, you know, great expertise, it is easy for me to design the molecular glues. Think about how the drug molecule works in the biological system. That’s where I can easily connect. That’s where my confidence has come that, you know, I can achieve, not only that, you know, I don’t need big laboratories to develop these drug molecules.

Nataraj Pagadala: You know, I can sit at home and design the molecular glues in on the computer with all my expertise. So, that’s where, you know, I started, I started this company because of all my expertise and also discovery of these drug molecules without having a laboratory spaces.

Grant Belgard: Have there been any particularly helpful pieces of advice from other founders or mentors that have changed the way you run the company?

Nataraj Pagadala: Actually, because, you know, there are very less people, you know, who are working on molecular glues. So, and as of now, apart from the very big companies, like [?], and also C4 Therapeutics, and also Chimera Therapeutics, and BMS, apart from this, I personally feel that, you know, I’m the only one who started as a startup with developing a molecular glues and developing a platform. Other than this, you know, till now, I did not see any kind of other founder developing a molecular glues till today.

Grant Belgard: What’s something about the founder-CEO role that you didn’t appreciate until you were actually doing it?

Nataraj Pagadala: Yeah, actually, as I’ve basically, you know, earlier, when I was doing, working in different companies, you know, at that time, I was, you know, my ideas was not taken into consideration. But as a CEO of the company, when I was developing this TriMatrix Analyzer platform, when I was developing this, you know, designing the molecular glues, you know, with a diagnostic kit, you know, that’s where actually people completely, you know, seeing me as a different person in terms of, because, you know, there are people who are well worth the experience from the last 10 to 15 years of experience. Even though they have so much of experience, they were unable to figure out how the ternary complexes, how the targeted protein degradation is happening in the biological system, you know.

Nataraj Pagadala: But as a CEO of the CEO of LigronBio, as within a short period of time, you know, when I was doing this, you know, then people, you know, are seeing me as a different exceptional person and then who can definitely deal these particular problems, you know, help the community and help the society for and also for future generations with Alzheimer’s and also other domestic diseases.

Grant Belgard: From your perspective, what are the most underrated skills for computational scientists who want to work closely with wet lab teams?

Nataraj Pagadala: With the wet lab teams, actually, we, this is basically a different complex, you know, biology. So I need, you know, I want to work with the people who are well-versed with, especially with the neuroscience one, especially with targeted protein degradation, who has experienced targeted protein degradation in terms of molecular glues, without that, it’s very difficult, you know, to understand, to understand and do the experiments in the, you know, in the laboratory without having a knowledge about the molecular glues are targeted protein degradation. So I prefer the people from this particular background, you know, if you want to work with, yeah.

Grant Belgard: Where do you think molecular glues will realistically be in 10 years? A niche modality or something more mainstream?

Nataraj Pagadala: Yeah, actually molecular glues, as of now, molecular glues are, are in the, in the high priority for different companies and also bigger companies like J&J. So because they are small molecules, as I said, you know, they are brain penetrant, gut penetrant, and also membrane permeable. So molecular glues are the first priority as of now, and also, till now, 24 billions of money was deployed in molecular glue development by different companies and also by different VCs. So molecular glues are the highest priority in, in under the next 10 years, molecular glues is going to occupy number one place compared to traditional drug molecules. Because, you know, as I said, you know, the effect of the molecular glue will be high, very high, 100 times more than a traditional drug molecule. So it is going to, it is the first number one priority in the next 10 years.

Nataraj Pagadala: And also, not only that, in the molecular glues are going to, you know, affect on the disease therapy, especially for the Alzheimer’s in the next 10 years, there is a high chances that a molecular glue therapy will come into existence for Alzheimer’s, for Alzheimer’s, and also help the progression of, you know, and also inhibit the progression of Alzheimer’s. That way, it is a stepping stone for, you know, reversing the Alzheimer’s. If that happens in the next 10 years, trust me that, you know, molecular glue therapy will also reverse the Parkinson’s and also will reverse the ALS and also all the devastating diseases, even the cancer progression. We definitely, we can reverse the cancer progression, and also we can inhibit the cancer progression, you know, 30 to 40 percent. That increases the lifespan of the patient and also the families who are affected with these devastating diseases.

Grant Belgard: Is there a misconception about molecular glues that you wish you could correct for everyone listening?

Nataraj Pagadala: Actually, yes. You know, basically, people think that, you know, molecular glues are very difficult to design. And also, molecular glues have a high serendipity and also off-target toxicity. This is what the people think about molecular glues. But, you know, if you design properly from right from the scratch, you know, and also, we can design a molecular glue with a high target. Because last 10 years, this is what is happening with the molecular glues. Whatever the target is, basically, they are designing, but ending up at the same targets repeatedly every time and showing a degradation. So, because there is some problem in designing the molecular glues. That is the reason why we can design the molecular glues without off-target toxicity, very easily, if you do right from the scratch in a proper way.

Nataraj Pagadala: So, this is the misconception that, you know, molecular glues cannot be designed so easily. That is, that is a misconception there for the different companies all over the world.

Grant Belgard: Finally, if listeners remember just one thing from this conversation, what would you want it to be?

Nataraj Pagadala: Yeah. LigronBio, we are unlocking the undruggable targets for Alzheimer’s and other neurodegenerative diseases with the molecular glues. So, this is where actually we are the pointers in the molecular glue discovery.

Grant Belgard: And how can listeners or potential investors connect with you to learn more?

Nataraj Pagadala: So, basically, through email and also with my website, you know, all the information is given in the website. And, you know, please contact me. If you want any kind of a collaboration, if you want any kind of a help in designing the molecular glues with our TriMatrix Analyzer platform, I’m here to help you in a very effective way. And also, we can reduce the time of research and the cost of your research. And we can design the molecular glue for sure within less than 36 months. So, all the details were given in the website. Please contact me. Or else, you know, my email is npagadala@ligronbio.com. And my cell number is 412-863-3812. Please contact with any of this, you know, medium. You know, I’ll be here to help you as much as I can. Thank you.

Grant Belgard: Nataraj, thank you for joining us.