molecular modelling


as possible in setting up virtual screening techniques and keep the feedback loop alive. When we identify a set of active compounds we feed what we learn back into the models,’ said Nabuurs. ‘One should be careful about using computational tools as a black box. You need to understand how to use them.’ Tis is something that Danish


cheminformatics company Molegro is well aware of in its product development plans. ‘What people like to do is to take the knowledge of the chemists – such as replacing a certain fragment of a molecule – and see the effect of this design change immediately,’ said René Tomsen, CEO and one of the founders of Molegro. ‘So far these techniques have been very advanced and required a lot of prior knowledge, so these types of tools are typically used by computational chemists. However, the trend is for soſtware to move to the area of medicinal chemists, making it easier for them to use.’


Industry factors Scoffin sees intelligent or iterative screening, where models are run and refined with input from experimental results, as the way to get the best from the tools. ‘Te computational process has to be part of the start of the process,’ he argued. However, there is a challenge that he identified; a communication gap between computational and synthetic chemists. ‘Techniques need to be understood across the two communities but both groups come from a different perspective,’ he noted. And the problem is exacerbated


because of the traditional hierarchy in pharmaceutical companies, he believes. ‘Medicinal chemists traditionally progress more quickly in companies. Synthetic medicinal chemists (or biologists, pharmacologists or biochemists) – rather than computational chemists – are likely to become head of R&D in these companies, so it’s almost baked into the system that you don’t have computational chemistry in the big picture.’ Other industry changes may not help


to bridge that communication gap either. Scoffin observed that cost-cutting measures have led many pharmaceutical companies to reduce their employee headcount in the area of computational chemistry. ‘Computational chemists are very expensive because they have big toys so there is an increasing trend towards taking that cost out of the running costs of the business,’ he explained. Cresset’s business model is to provide both soſtware and consulting services and


www.scientific-computing.com


the company has noticed a shiſt towards the consulting side of its business in recent years. ‘Pharmaceutical companies still need and bring in expertise so we drop consultants into a company at the point they need them – oſten computational chemists who have set themselves up as one-man-band consultants when they were made redundant by those pharmaceutical


frame because of computing capacity. Tere is still a limitation in terms of turnaround time too. Te soſtware needs to be able to provide a rapid answer, not necessarily the best answer.’ Tis is a challenge that Molegro has


been working on with its soſtware as well. ‘Te aim is to reduce the time spent doing simulations, but at the same time keep


WE’VE COME ON IN LEAPS AND BOUNDS IN TERMS OF SHEER COMPUTATIONAL CAPACITY AND ARE DEFINITELY SEEING THE BENEFITS OF THAT


companies, and where we can act as the business development front-end for a group of such experts,’ he said. Tere are other trends too: ‘At the moment


the overall market is in turmoil, with a shiſt in emphasis from large companies back down to small- and medium-sized companies,’ Scoffin added. ‘It is easy to look at the overall pharmaceutical market and be depressed about headcounts going down, but the research is still going on; just in a different way. Today, discovery is going on in academic and not-for-profit settings and charities, as well as pharmaceutical companies. Tere is a need for flexibility.’


Technical challenges Tere are still challenges and opportunities with molecular modelling tools too. According to Krieger of YASARA Biosciences: ‘Today’s docking soſtware is already pretty good at sampling (generating plausible receptor-ligand complexes), but two major difficulties remain unsolved: First, the accurate prediction of induced fit, how the receptor adapts while binding the ligand. And second, the reliable prediction of the free energy of binding, which in reality includes many more contributions than current soſtware tries to consider. For example, subtle entropic and quantum effects.’ ‘We’ve come on in leaps


and bounds in terms of sheer computational capacity and are definitely seeing the benefits of that in terms of the number of molecules we can look at and the detail, but there is still a limitation,’ agreed Scoffin of Cresset. ‘We could do quantum chemistry calculations, but we can’t do that over a series of molecules in a reasonable time


a certain level of accuracy,’ noted René Tomsen of the company. ‘We’ve recently introduced a way to run simulations on graphic cards. Tis has increased the speed by a factor of 30. Previously, one model of a protein and a ligand typically took a few minutes, but with a graphics card it takes a few seconds.’ Such developments are needed as the


demands on computational tools increase. ‘Tere are many degrees of freedom. You need to have a computer algorithm to search possible solutions and a good scoring solution that can score and predict binding modes.’ In addition, he identified challenges in, for example, how to handle the flexibility of proteins and predict binding affinity. Another area of interest for Tomsen is


modelling water in the systems. Proteins and their potential ligands are soluble in water, but this has been a difficult thing to model accurately. Tomsen and collaborators at Aarhus University, Denmark, have recently published a paper about incorporating water molecules in protein-ligand docking. Tese themes were echoed


Further information:


Aarhus University www.au.dk/en


Cresset BioMolecular Discovery www.cresset-group.com


Lead Pharma www.leadpharma.com


Molegro www.molegro.com


Scripps Research Institute www.scripps.edu


YASARA Bioscience www.yasara.org


in discussions at the recent Discovery Chemistry Congress 2012 held in Munich, according to Nabuurs of Lead Pharma. ‘Impressive progress has been made,’ he said. ‘Future trends will include better integration of tools and looking broader than protein-ligand interaction to really make the transition from animal trials to human successfully.’ ‘I don’t see clear limitations


with computational tools per se,’ he concluded. ‘It’s up to the creativity of the person using the tools to get the most out of them and use them in way that produces something useful.’


APRIL/MAY 2012 47


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