Imagine trying to jam a lock with a key that almost fits. It may work for a while, but eventually the lock finds a way to resist. A similar challenge exists in treating acute myeloid leukemia (AML), an aggressive blood cancer. Many current drugs target a protein called FLT3, a molecular switch that drives the uncontrolled growth of cancer cells. However, these drugs often lose their effectiveness as the protein changes over time or the drugs fail to bind strongly enough.
A recent study by NCBS and UAS, Bengaluru takes a different approach to this paradox. Instead of searching for an entirely new drug, the team redesigned an existing FLT3 inhibitor to make it bind more tightly and remain more stable. Their computational study suggests that this redesigned molecule could serve as a stronger starting point for future anti cancer therapies.
“Proteins like FLT3 are not rigid structures. They constantly flex and shift between different shapes. In healthy cells, FLT3 helps regulate the production of blood cells. But in nearly one-third of AML patients, mutations leave this molecular switch permanently turned on, causing immature white blood cells to multiply uncontrollably,” says Dheemanth Regati, one of the lead authors of the study. “Although several FLT3-targeting drugs are already available, many face familiar problems,” he added.
Some of them interact with other proteins, leading to unwanted side effects, while others gradually become less effective as cancer cells evolve resistance. Designing molecules that latch onto FLT3 more securely is therefore an important goal in developing long lasting treatments.
Rather than starting from scratch, the researchers chose an experimentally known FLT3 inhibitor named CHEMBL4444839 as their template. Using structure-based drug design, they systematically modified different parts of the molecule and evaluated thousands of possible variations using computational tools.
“One modification stood out. By introducing a small fluorocyclobutane group the researchers produced a new analogue predicted to bind FLT3 more strongly than the original molecule,” says Dheemanth.“But stronger binding alone is not enough. Drug candidates must also behave well inside the body. We assessed whether the redesigned molecule showed favourable properties such as absorption, metabolism, toxicity and stability. Compared to the parent compound, the analogue was predicted to have lower toxicity, improved drug-like properties and better metabolic stability, making it a more promising therapeutic candidate,” he added.
The research team then asked a more demanding question: would the molecule stay attached to FLT3 under realistic biological conditions?
To answer this, they used molecular dynamics simulations, a technique that models the movements of atoms over time. Instead of looking at a static snapshot, these simulations allow scientists to watch proteins and drug molecules "dance" together over hundreds of nanoseconds, revealing whether their interactions remain stable.
The redesigned inhibitor consistently performed better than the original. It formed additional interactions with important regions of the FLT3 protein and reduced fluctuations in parts of the protein that are critical for its activity. Throughout the simulations, the protein-drug complex remained more compact and stable, suggesting that the modified molecule could keep FLT3 locked in its inactive state more effectively.
"Our strategy was to improve an existing molecule rather than reinvent the wheel," explains Dheemanth. "By making carefully chosen structural changes and evaluating them through multiple computational approaches, we identified a design that appears more stable, binds more strongly and has improved drug-like characteristics."
The team also calculated the binding free energy of the two molecules. Lower free energy indicates a more favourable interaction, much like a magnet that grips more firmly. Here too, the analogue consistently outperformed the original compound, reinforcing the idea that it may inhibit FLT3 more effectively.
“When there are off-target effects or drug resistance, rather than search for newer inhibitors, we employed rational drug design to improve starting from the existing lead molecule. Here, the quest is really to identify analogs which would outperform the lead molecule in all desirable properties. Further research, to learn if this new small molecule is indeed effective, would require function validation through assays and so on,” says Prof. R Sowdhamini, the Principal Investigator of the study.
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