Hausheer's team developed a theory regarding the toxicity of platinum-based drugs. They speculated there were two forms of platinum: one responsible for antitumor activity, the other for toxicity. To make an ideal protective agent, Hausheer says, they needed to identify one agent that would intercept and react very specifically with the toxic platinum species and bind tightly to it, thereby inactivating it. "We weren't looking at a whole protein structure and trying to make a key that fits into the lock. We were trying to intercept a molecular species that may differ by only one or two or three atoms," he says.
Platinum has what's known as relativistic error — a quantum mechanics problem — introduced by the core electrons in the atoms approaching the speed of light. You cannot use approximations to determine position, binding, energy, and so on. Simulation helped provide the answer.
"We constructed a method of understanding the cis-platinum chemistry from a computational point of view," explains BioNumerik chemist Pavankumar Petluru. "Based on the simulation, we then proposed that the mono-hydrated platinum is the toxic species. This was the key piece of evidence."
Bench chemists synthesized the compounds and tested them. Combining additional simulations with spectroscopic measurements, re-searchers proved their hypothesis and predicted that a group of sulfur compounds could inactivate the platinum. Other problems had to be overcome — selected sulfur groups are also toxic — but, ultimately, BioNumerik solved the problem using its blend of simulation and wet lab.
The result is BNP7787, a compound that effectively intercepts the toxic species of platinum and taxane drugs, dramatically reducing their toxicity. Early results look promising: Last May, BioNumerik — and partner Grelan Pharmaceuticals — presented a BNP7787 Phase I trial (in Japan) at the annual meeting of the American Society of Clinical Oncology. Hausheer hopes to garner approval as early as 2005. BioNumerik has even manufactured 1.8 metric tons of the drug under GMP.
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