How did you get interested in Medicinal Chemistry?
My first encounter with medicinal chemistry was during my studies of biochemistry and medicine. I was immediately fascinated by the fact that small molecules can modulate complex living systems, and was hooked right from the start. Understanding the interactions between effector molecules and their receptors remains one of my scientific passions.

What was the topic of your PhD project?
During my PhD project at the Freie Universität Berlin I developed the first computational approach to autonomous ‘generative’ molecular de novo design with artificial neural networks. These were humble beginnings compared to today’s technology, but it was all there in the early 1990s already.

Where did you have your postdoc position?
I had the great opportunity to visit several laboratories as a Boehringer Ingelheim Fellow, including the M.I.T. in Cambridge, MA (with Prof. Schimmel), the Benjamin Franklin Clinic in Berlin (with Prof. Wrede), the University of Stockhom (with Prof. von Heijne), and the Max Planck Institute of Biophysics in Frankfurt am Main (with Prof. Schulten).

What are your current research interests?
My current research focus is on the development and application of drug discovery methodology with artificial intelligence. We specifically aim to capture the diversity of natural products by help of machine learning, and use these models to generate synthetically accessible mimetics with the desired pharmacological properties.

What do you like most in your job?
The best about my job is the freedom to explore new things every day. There is so much to discover.
My position as a university professor includes teaching and research, but also administrative duties. In addition, I always seek the interaction between my research group and the pharmaceutical industry which helps us focus on the relevant questions for the application of our methods.

What do you consider your biggest achievement in your scientific career?
My greatest scientific achievement may be my persistence to continue developing and applying ‘artificial intelligence’ methods to medicinal chemistry over a period of three decades, against all odds.

Which scientist do you admire the most and why?
If I had to pick, I would probably choose Fridtjof Nansen, whose scientific achievements and humanitarian work I very much admire. Scientists are diplomats after all.

Which paper of yours you are the proudest of and why?
I had to think about the answer to this question for a while. To me, scientific papers are no more than protocols summarizing one’s thoughts and the state of knowledge at a given time. I am not ‘proud’ of a paper per se, but would probably pick a publication from 1994 (Biophys. J. 66, 335-344), despite all of its shortcomings. In this original publication we present the first adaptive molecular design algorithm that was able to generate new bioactive molecules (bioactivity of the de novo designs was confirmed in a later study), learn from experience, and generalize. This concept still provides the template for contemporary generative de novo design methods and active learning approaches in medicinal chemistry.

Did you experience any unfair situations during your scientific career?
Much could I say about this topic. I have experienced personal and scientific breakdowns facing vile treatment and spitefulness by fellow scientists. Importantly, I learned that the perception of unfair treatment must not cloud one’s own judgement, you have to roll with the punches, and that humility truly is a virtue.

Which field of medicinal chemistry do you consider the most promising in the future?
I am convinced that the advance of artificial intelligence will enable a renaissance of nature-inspired medicinal chemistry with a fresh view on natural products and their mimetics, and the emergent features of complex adaptive systems. ‘Learning from nature’ with this new twist will offer ample opportunity for future medicinal chemistry.

What would you guess to be the next major breakthrough in medicinal chemistry?
My best guess is that we will learn something rather unexpected about virus-host interactions that will lead to innovative treatments of viral infections.

How did you get interested in Medicinal Chemistry?
The research areas that I was involved in for my master and PhD theses work and postdoctoral training were not Medicinal Chemistry. However, I was fortunate to be trained in two fields, organic chemistry and mechanistic enzymology, by some of the greatest pioneers and erudite scientists in these fields. So when I began my own lab and launched a program to develop technologies that would allow researchers to decode the biological behavior of natural reactive electrophiles with precision, I became more and more aware of how these accumulating data in this field and our own insights directly impinge on covalent drug design. So we started thinking about understanding the precise mode-of-action of emerging electrophilic pharmacophores. This avenue ultimately drew me further into medicinal chemistry and I became very excited about how our work can directly contribute to this field.

What was the topic of your PhD project?
I did my PhD with Professor David A. Evans at Harvard University, USA - The topic was In the area of asymmetric catalysis & new reaction discovery: more specifically, ‘development and applications of organosilanes as stable, environmentally-benign & versatile cabanion equivalents’.

Where do you work at the moment and what is your current position?
At EPFL, I am an associate professor and the director of the laboratory of electrophiles and genome operation (LEAGO) https://leago.epfl.ch

What are your current research interests?
They have always been rather broad and deeply interdisciplinary. For the most recent years/near future, we are keenly pursuing new knowledge regarding reactive electrophile/covalent-ligand signaling at individual protein-and-ligand-pair-specific and context-specific manner. In parallel, we are also actively researching unexpected moonlighting functions of disease-relevant proteins. In both directions, we strive to see comprehensive mechanistic understanding both in vitro and in relevant living models.

What do you like most in your job?
The simultaneous opportunity to be an educator and an innovator: in terms of the former, the chance to inspire and educate some of the young minds; for the latter, ability to bring something crosscutting to the table that has potential to improve human life and medicine.

What kind of skills your job requires?
In science: thinking, critical evaluation (usually questioning conventional wisdom), innovating non-conventional solutions, seeing the big-picture, finding impactful/relevant problems to work on and designing most-insightful experiments, and last but not least, having a strong work ethic. In team-leading and all other services, good mentors/educators manifest excellent communication skills, team-playing, empathy, selflessness, and giving opportunities for the trainees/mentees to thrive in challenging environments, helping mentees prepare for the good times and the tribulations of the next-step of their careers.

What do you consider your biggest achievement in your scientific career?
Over the 8-year-span of our lab thus far, it would most likely be the opportunity to have offered to the field the previously-inaccessible ability to quantitatively track the ramifications of non-enzyme-assisted covalent protein modifications by reactive electrophiles. This is the idea behind our T-REX technology, and the underlying concept was not thought of before. With T-REX and related techniques, we began to accumulate paradigm-shifting insights into how electrophile-/covalent-ligand-guided signaling functions at low-occupancy and how these individual ligand-guided events control decision-making.

What is the most embarrassing thing you did in the lab while doing experiments?
During my graduate school, shaking a litre-scale separatory-funnel while working up a Shapiro reaction (that was needed for me to prepare a particular vinyl-silane substrate precursor), resulting in N2(g)-driven explosion. Clearly, I wasn’t engaging my brain there.

Which scientist do you admire the most and why?
Several living and deceased, but perhaps the late Dorothy Hodgkin because I was an undergraduate chemist at Oxford University, Somerville College, where Hodgkin once studied as well as tutored chemists. I thus felt I was directly inspired by Dorothy Hodgkin’s scientific legacy. Furthermore, as a student having not had access to proper education before my arrival to the UK at 17, her legacy made a long-lasting impact on my future career goals since my high-school days in the UK.

Did you experience any unfair situations during your scientific career?
It is surprising to me how many of the common unfair situations we find ourselves in are a projection of our own, or someone else’s interpretation of, our own expectations, situation, or status. It is also surprising how the same gripes are pretty common across different scientific career stages/geolocations/situations. So, the answer is, of course, yes, there are many unfair situations out there; and I still frequently encounter situations I consider to be unfair, both to me, and to others. It is just that the ways these manifest, and to some extent what I choose to tolerate that have changed. But regardless of your situation, I think it is important to keep your chin up and find effective ways to overcome/preempt such situations, especially if you’re in a leadership/group-leader role as this is important for students/trainees. At the end of the day, intelligence along with facts should always (though sadly they do not always) win over.

Which field of medicinal chemistry do you consider the most promising in the future?
Medicinal chemistry is one of the few industries where billions, or even trillions, of dollars are exchanged every year trying to turn something off. We’ve spent years turning enzymes off. Now we’re trying to do the same with scaffolding proteins, oncogenes, shallow binding pockets, and so on. We really need to start to look to mining the resources of the proteome actively (i.e., turning something ON), learning how to harness large gains at small loading, for instance. Such power would be revolutionary.

What would you like to ask from other medicinal chemists?
In one phrase, the answer would be ‘improve real-world relevance’. I think that in this field, one can often get carried away with a lot of in-tube studies or using less relevant models, optimizing Kd with not much else, etc. Once some initial hits/lead data have been obtained, it is quite important to move onto more relevant models/start to answer most relevant questions. As a field, we can do better by not being too bogged down with monodimensional readouts, and by being more broad-minded, having a forward-looking outlook, and taking a multi-disciplinary approach. Prior to initiating a project/model system or an assay, it is first useful to ask to what extent what we are designing/pursuing is of relevance to real-world scenarios. We are better off not pursuing a project/set-up/assay, only because of convenience and of it being within our comfort zone.

What would you guess to be the next major breakthrough in medicinal chemistry?
It would be how we understand and manipulate/alter signaling and pathway intersections, and ultimately cell fate/decision making, through gain-of-function activities, i.e., when a ligand binds a target only at low-occupancy. Many drugs and mechanisms-of-action are proven quite effective at sub-stoichiometric target engagement. A similar low-occupancy idea also bodes well for targeting essential genes where complete inhibition is disastrous. However, neither from systems-level or mechanistically, have we even scratched the surface of selectively profiling such proteins (and ligand frameworks) that can be responsive to such gain-of-function druggability.