By Dr Neil Taylor
As Australia and England once again contest an Ashes series, the familiar rhythms of Test cricket (Perth aside) are back on display. Five-day matches, shifting conditions and long periods of pressure remind us that outcomes are rarely decided quickly. Success comes from patience, preparation and the ability to adapt as the game unfolds.
That mindset will feel immediately familiar to anyone involved in structure-based drug design.
At first glance, cricket and medicinal chemistry seem worlds apart. Look closer, however, and the parallels are striking. Both are intricate contests where early promise can be misleading, conditions change without warning, and long-term success hinges less on fleeting moments of brilliance than on sustained, considered decision-making.
In Test cricket, the pitch defines the contest. Groundskeepers at Lord’s or the MCG prepare wickets with specific characteristics, and every crack, groove and patch of grass shapes how the game is played.
In structure-based drug design, the target protein plays a similar role. Medicinal chemists must understand every groove, pocket and surface of their protein target. The binding site is like that critical area just outside off-stump, knowing exactly where to pitch your delivery makes all the difference. Without this level of understanding, compound design quickly becomes guesswork rather than strategy.
Lead compounds are your opening batsmen. They show promise, get you on the board, but rarely do they win the match on their own.
You send them in to test the conditions to see how they behave, where they struggle and what they reveal about the target. Some get out early, falling to toxicity or poor pharmacokinetics. Others survive long enough to lay the foundations for the innings ahead. Their real value lies not just in early performance, but in what they teach you about the game you’re playing.
Drug discovery, like Test cricket, is an iterative contest. You don’t win with a single ball, and you don’t design a drug in a single optimisation cycle.
Each round of design, synthesis and testing builds incrementally. Sometimes you score boundaries, making meaningful gains in potency or selectivity. Other times you defend carefully, improving exposure or safety without sacrificing binding affinity. Progress depends on reading the conditions and responding intelligently, not forcing outcomes.
Those conditions are rarely static. Flexible protein loops behave like a variable-bounce pitch. Water molecules in the binding site can be as unpredictable as swing bowling on an overcast day. What worked yesterday may not work tomorrow, and success comes from adapting rather than insisting on a fixed plan.
This is where structural biology changes the game. X-ray crystallography and cryo-EM are the Hawk-Eye and UltraEdge of drug design. They reveal what actually happened at the molecular level, not what models predicted or hoped for. Did the compound bind where you thought it would? Did the protein shift into a different conformation? Were key interactions preserved or lost?
In practical terms, these techniques allow teams to:
By removing guesswork and replacing it with atomic-level evidence, structural biology fundamentally reshapes how compounds are refined.
Drug designers aren’t just competing against a protein target, they’re competing against billions of years of evolutionary refinement. Proteins have evolved defences: conformational flexibility, desolvation penalties and entropy costs that constantly move the goalposts.
It’s not unlike the Ashes rivalry itself. Every series presents new conditions, new players and new strategic challenges. Respecting that complexity is essential. Trying to overpower it rarely ends well.
Selectivity adds another layer of difficulty. Designing a compound that binds tightly to its intended target while ignoring closely related proteins mirrors the selection dilemmas faced by cricket captains. Off-target effects are the equivalent of fielding weaknesses; often invisible early, but costly over time. Precision matters more than brute strength.
An Ashes series demands sustained excellence across five Tests. Drug discovery often takes ten to fifteen years from hit identification to market. Along the way, many promising ideas fall away. Compounds that looked perfect in silico may fail in animal studies, the equivalent of a talented batsman who dominates county cricket but struggles at Test level. Back to the drawing board.
The eventual successes are built through resilience, learning and persistence. As every Ashes series reminds us, Test cricket rewards those who respect complexity and think beyond quick wins. Conditions evolve, early advantages fade and progress is often incremental rather than spectacular.
Structure-based drug design follows the same pattern. Targets change behaviour, assumptions are challenged and apparent breakthroughs must withstand sustained scrutiny over time. In both endeavours, the sweetest victories come from meticulous preparation, intelligent adaptation under pressure and, occasionally, a moment of inspired genius that no amount of planning could predict.
Protein targets are dynamic and complex, and early hypotheses are often incomplete. Iteration allows teams to test assumptions, learn from unexpected results and refine compounds based on observed behaviour rather than prediction alone.
Techniques such as X-ray crystallography and cryo-EM show how compounds actually interact with targets at the atomic level. This removes guesswork, helps explain failures and guides more informed optimisation decisions.
For more reflections on structure-based drug design, scientific workflows and
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