Research Scholarship

Interactive drug-design: using advanced computing to evaluate the induced fit effect

Drug discovery is a time consuming, expensive process and is often a very frustrating experience for the researchers involved. For these reasons new drug design approaches and methodologies are constantly developed in order to reduce the time and costs of this process. Recently, interest has increasingly been focused on computer-based techniques and molecular modelling, which allow the design and evaluation of novel potential drugs in silico before being prepared in a laboratory. The development of many modelling software packages is oriented toward limiting the human intervention, considered to be the bottleneck of the process. The user carries out preparation of the input and analysis of the output, leaving the rest of the discovery process to the computer. Indeed, the use of these methodologies has led to many successes, but it would be fair to ask us if a process that relies mostly on computer pseudo-knowledge whilst, marginalizing researcher knowledge, could be really considered a rational approach. An interactive informed human intervention in a computer simulation could significantly improve the results obtained and this is particularly evident in de novo drug design applications. Following this idea, we have developed a novel immersive molecular modelling simulator where the user uses an haptic device to probe a biological target and its interactions with a potential drug, feeling the forces and molecular interactions on his/her hand while having complete three dimensional visual feedback. The movements of the user’s hand are tracked in real time and used to steer the simulation.
 
We are proposing to further evolve this project, exploring the possibility to include some degree of protein flexibility into the drug design simulations. Currently, our software, like many de novo and molecular docking packages, treats the small molecule examined as flexible and the biological target as rigid. This is a significant approximation to the real scenario, where the target protein undergoes some conformational changes upon binding of a small molecule. The simulation of such 'induced fit' would require computationally expensive calculations and we would tackle this issue by parallelising the code and by using high performance computing facilities (ARCCA). Initially, we will investigate the possibility to use the software on the main cluster (MERLIN) using a dedicated partition. We will then focus on the development of the code on GP-GPUs architecture. In Cardiff we have such hardware, namely an NVidia Tesla and a ClearSpeed CATS. Such approaches would enable us to develop a novel computer-based drug design approach that takes into account the protein flexibility in molecular modelling simulations, thus generating more accurate results, based on an interactive, user-friendly, haptics-driven interface. The project will lever on the expertise (both industrial and academic) of applying acceleration hardware to existing applications, available in both the School of Computer Science & Informatics and in ARCCA, enabling the interactive haptic-driven solution to be both cost-efficient and power-efficient through its use of specialist hardware.

ARCCA also offers a rage of unique training courses on various aspect of high performance computing and the student will have the chance to benefit from those, along with the other courses on transferable skills offered by the School of Pharmacy and the Graduate Schools and some more specific courses offered by the School of Computer Science & Informatics.

The project proposal merges new techniques available from Computer Science & Informatics in the field of computer- aided drug design, namely: haptic / touch interfaces and reconfigurable computing. This combination is novel to the field of drug discovery, which will enhance the current techniques normally applied in drug design. This proposal enables collaboration between Computer Science & Informatics and Medicinal Chemistry to investigate novel interaction approaches which are only possible with the latest advances in high performance computing.

All applications for admission to research programmes must be submitted direct to the University, either using the University’s on-line admissions service or by submitting a paper application form which can be downloaded from the University’s webpages.