The identification of protein–ligand interactions at high resolution is a central aim in structure-based drug discovery. Advances in microcrystal electron diffraction (MicroED) now enable structural determination from microcrystals, eliminating the need for larger ones.

In this study, Lin et al. developed a workflow combining cocktail soaking of protein microcrystals (thermolysin and proteinase K) with automated MicroED to accelerate ligand screening. Microcrystals were fragmented via sonication, soaked with known ligands, and analyzed by MicroED. High-throughput data collection (7 min/crystal) allowed rapid resolution of binding sites, even for weak-affinity ligands.

Electron density maps confirmed ligand binding consistent with prior studies, though alternative poses were observed for proteinase K. By integrating cocktail soaking and automated MicroED, the authors present a platform for efficient structural screening, enabling direct visualization of ligand–protein complexes at near-atomic resolution. This approach is particularly valuable for microcrystals incompatible with X-ray diffraction.

While this study presents a promising platform that successfully integrates cocktail soaking with automated MicroED for ligand screening, broader validation across diverse protein targets and ligand classes will be essential to establish its general utility in structural drug discovery.

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How did you get interested in Medicinal Chemistry?

I developed a general interest in the interface of organic chemistry, biology and pharmacology during my pharmacy undergraduate degree. This led me to seek specific post-graduate opportunities in this area, including an MSc in medicinal and biological chemistry at the University of Edinburgh, a PhD in organic chemistry at Rhodes University, and a Post-doctoral Fellowship at the University of Stellenbosch. These combined experiences as well as the opportunity to interact with students and academics across related disciplines helped me to develop my specific interests in chemical biology and medicinal chemistry.

Where are you currently working and what is your current position?

I am currently an Associate Professor of Organic Chemistry at the University of Cape Town. 

What are your current research interests?

The main interest of our group is to apply skills in organic synthesis and biophysical chemistry (particularly native mass spectrometry) to investigate ‘difficult-to-access’ and underexplored chemical space. Examples of this include characterization and modulation of transient protein-protein interactions and small molecules, which are confined to the extracellular environment. The aim of this work is to develop creative solutions for addressing neglected diseases in Africa, particularly those without validated pharmacological targets. Our recent focus has been to develop small molecules which modulate the interaction between the Hsp90 chaperone protein, and its co-chaperone HOP as a strategy for developing inhibitors onco-viruses (e.g. KSHV).

What do you like best about your work?

I enjoy the open-ended nature of academic research. I always find it amazing, how curiosity-driven research projects don’t end up progressing exactly as you planned. Somehow, the process of conducting well executed experiments produces unexpected results and delivers different but equally important scientific insight. 

What kind of skills does your work require?

Typically, our contributions to collaborative projects require skills in synthetic organic chemistry and /or analytical chemistry skills. Our group also place high value on communication, teamwork and cooperation. In addition, being able to problem-solve and figure out what is going on when ‘something weird’ happens is very important.

What do you consider your greatest achievement in your scientific career?

A few years back I was the recipient of a Royal Society Future Leaders – African Independent Research (FLAIR) Fellowship. This fellowship acted like a springboard for advancing my science and my career in general.

Which of your papers are you most proud of and why?

These would have to be the series we published on the Hsp90-HOP PPI, where we developed native mass spectrometry methods to identify PPI modulatory compounds, and further developed these to facilitate PPI interfacial characterisation. This led to a very satisfying translational result, where we demonstrated that our Hsp90-HOP PPI inhibitory compounds disrupted the activation of KSHV lytic replication, thus providing the first potential validation of this PPI as a host-based target for KSHV drug discovery. From a basic sciences perspective, it represented an important step in understanding viral interactions with the host regulatory machinery and is a key idea we are taking forward into our future chemical biology programme.

What are the features of a successful PhD student or postdoc?

Unfortunately, failure is a big part of research. Students and post-docs who are not closed books, but to seek help when it is needed, communicate success and failure to their advisors regularly and understand that failure is not a reflection on them personally, tend to be more successful.

What advice would you give to someone who wants to know more about your field? 

Join the EFMC mailing list! 

What would you like to ask from other medicinal chemists?

Please keep in mind that insightful science is still achievable using ‘old-school’ approaches. Particularly in resource constrained environments. Judge the actual science, not the perception.

What are your recommendations for a book, podcast, website, blog, YouTube channel or film?

I really enjoy the Naked Scientists Podcast. They are experts in distilling the essence of cutting-edge science and keeps me abreast of many different fields.

Which scientist do you admire the most and why?

Aaron Klug, and not just because he is South African. His ability to harness insights in fundamental chemistry and physics to study viral structure, is for me the essence of chemical biology.

Which field of medicinal chemistry do you consider the most promising for the future?

Medicinal chemistry and chemical biology together have made some outstanding dogma breaking progress in the last two decades. Introducing covalent warheads and the large non ‘drug-like’ molecules for proximity-based pharmacology are two particular successes. I think this dogma breaking trend will continue into host-based targets for antimicrobial drug discovery for numerous infectious pathogens.

What would you expect to be the next breakthrough in medicinal chemistry?

The role of drug design in personalised medicine will be fascinating to follow.