Researchers at the University of Bradford have made a breakthrough in the prediction of the crystal structures of small organic molecules as part of an international scientific competition.
(ag/ehj) – Drs Frank Leusen and John Kendrick from the Institute of Pharmaceutical Innovation (IPI) at the University of Bradford, collaborated with industrial partner Dr Marcus Neumann of Avant-garde Materials Simulation in Paris in the Blind Test in Crystal Structure Prediction, organised by the University of Cambridge and hosted by the Cambridge Crystallographic Data Centre (CCDC).
The team have met the challenge by correctly predicting the crystal structures of all four Blind Test compounds using computational methods without any experimental input.
Crystal structures describe the periodically repeating arrangement of molecules in a material and determine many of a material’s properties, such as solubility, dissolution rate, hardness, colour and external shape. The ability to predict crystal structures could revolutionise the design of materials with novel properties.
In particular, the pharmaceutical industry would benefit from reliable methods of crystal structure prediction because pharmaceutical molecules are prone to crystallise in more than one crystal structure (or polymorph), depending on the conditions under which the molecule is crystallised. The specific polymorph that goes into a formulation must be strictly controlled to ensure consistency of delivery to the patient.
Dr John Kendrick, Senior Researcher at the Institute of Pharmaceutical Innovation at the University of Bradford, said: “We are tremendously excited about this result. The success of our approach begins to answer many questions which have been posed over the years, and opens up several new avenues for leading-edge research.
“Having proven that the crystal structures of small organic compounds can be predicted reliably, we now face the challenge of predicting the relative stability of polymorphs as a function of crystallisation conditions to really capture the effect of temperature and solvent.”
The team applied a new computer program, GRACE, recently developed by Avant-garde Materials Simulation, and predicted the crystal structures of all four test compounds correctly. Their results are a significant improvement over the outcome of previous Blind Tests. The other 14 participants in the event, which included ETH Zürich (Switzerland), the Pfizer Institute at Cambridge University (UK), University College London (UK), Cornell University (USA) and Purdue University (USA), correctly predicted none, one or two of the crystal structures.
Many approaches to the problem have been developed and these have been evaluated over the years in the Blind Tests. Fifteen research groups who had been developing methods for predicting crystal structures of organic molecules in the latest test were challenged to predict four recently determined crystal structures given only the chemical diagram of the molecules and conditions of crystallisation, with three predictions allowed per crystal.
The results of previous blind tests, in 1999, 2001 and 2004, demonstrated that the crystal structures of small organic molecules are hard to predict, The rates of success were low and no one method was consistently successful over the range of types of molecules studied.
Dr Graeme Day of the University of Cambridge, who co-ordinated this year’s challenge, said: “The results of this year’s test reflect significant development over the past few years. Things looked much less encouraging last time we held a blind test, but crystal structure prediction can now be seen as a real tool to be used alongside experimental studies, when designing new materials or developing a pharmaceutical molecule.”
Dr Marcus Neumann, author of computer program GRACE for crystal structure prediction, said: “Obviously we are delighted with these results but there is still plenty of room for improvements. Over the next few years the range of applicability will gradually extend towards more and more complex compounds such as highly flexible molecules, solvates and salts.”
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