Kevin Williams; Elizabeth Bilsland; Andrew Sparkes; Wayne Aubrey; Michael Young; Larisa N. Soldatova; Kurt De Grave; Jan Ramon; Michaela de Clare; Worachart Sirawaraporn; Stephen G. Oliver; Ross D. King

“ However, it is also conservative, as the difficulties in physically creating structurally diverse libraries means that the probability of an individual compound being a novel structural hit probably decreases with the size of the library, which means that the savings are probably much greater for large libraries. Therefore, intelligent screening is more cost-effective with larger libraries, more valuable compounds and fast cycles of assay screening and testing—this is the standard regime for pharmaceutical screening, suggesting that adoption of intelligent screening is economically rational. ”

“ Eve's yeast synthetic biology assay results indicate that TNP-470 has high activity against P. vivax DHFR (figure 5) . To further confirm that DHFR is an additional target of TNP-470 we performed DHFR enzyme inhibition assays [27] . We observed that P. vivax DHFR was 1000-fold more sensitive to TNP-470 than its human counterpart; the drug's IC50 for the parasite enzyme being 0.16 μM, compared to more than 165 μM for human DHFR. This is consistent with the results of Eve's assays and suggests that our approach identified a bona fide DHFR inhibitor with improved selectivity. ”

“ The advances that distinguished Adam from other complex laboratory systems (such as high-throughput drug-screening pipelines and X-ray crystallography crystal-screening systems) was its artificial intelligence (AI) software, its many complex internal cycles, and its ability to execute high-throughput individually planned cycles of experiments.
In this paper, we demonstrate the viability of the Robot Scientist ‘Eve’ in drug discovery. We focus on finding lead compounds for neglected tropical diseases. However, the principles and methods used can be generally employed. ”

“ Abstract There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist ‘Eve’ designed to make drug discovery more economical. ”

“ The software to parametrize growth curves for the different yeast strains in each well was taken from the Adam project [9] . The main parameters are estimated maximum growth, doubling time and lag time. These growth parameters were then transferred to the AI QSAR software. Software was also written to coordinate library-screening, and to plan hit-confirmation. This was also integrated with the AI software so that the active learning algorithm could select compounds to test. ”

“ Early stage drug design. The contribution of standardized synthetic biology assays and Eve to a cheaper faster drug discovery pipeline. (Online version in colour.) The standard way to improve the economics of a process is through automation and standardization [7] . The use of automation has been enthusiastically pursued by the pharmaceutical industry. Much of this effort has gone into making library screening faster, especially through miniaturization, with the result that high-throughput robotic systems now routinely screen millions of compounds in library screens [5] . ”

“ Eve's robotic system is capable of moderately high-throughput compound screening: greater than 10 000 compounds per day, depending on the length of time taken to assay compounds. Eve is designed to be sufficiently flexible that it can be rapidly reconfigured to carry out a number of different biological assays, using fluorescence, absorbance or cell morphology as read-outs (figure 2) . ”

“ In this way Robot Scientists can automate high-throughput hypothesis led research. Robot Scientists are also well suited to recording scientific knowledge: as the experiments are conceived and executed automatically by computer, it is possible to completely capture and digitally curate all aspects of the scientific process. [9] . The first Robot Scientist ‘Adam’ was designed to plan and execute yeast microbiological experiments. ”

“ Such compounds are ‘true’ for the assay. They are unlikely to be cytotoxic, as that would imply that the yeast strain expressing the human enzyme would also be inhibited. However, this does not completely remove the probability of human cytotoxicity as there could be off target effects specific to human cells, therefore further studies are required. ”

“ Although the costs of drug discovery are substantial, they are relatively small compared with later stages in development. Such arguments tell against increased automation and standardization in drug discovery making much economic difference. ”

“ In this model the net utility is the cost saving due to not screening compounds, minus the cost due to missing any hits, minus the cumulative cost of the number of active learning cycles performed. Active learning was applied to the seed input data, and predictions made to produce simulated learning curves. ”

“ New drugs are generally slow (more than 10 years) and expensive (more than $1 Billion) to discover and develop. Consequently tropical diseases, malaria, schistosomiasis, Chagas' disease, etc., which kill millions of people and infect hundreds of millions of others are ‘neglected’ [1] , [2] ”

“ Active learning with statistical models. J. Artificial Intell. Res. 4, 129–145 .↑ Lounkine E, et al. 2012. Large-scale prediction and testing of drug activity on side-effect targets. Nature 486, 361–367 (doi:10.1038/nature11159) pmid:22722194↑ Vogel HG. 2002. Drug discovery and evaluation: pharmacological assays. Berlin, Germany: Springer.1 2 Schneider G. 2010. Virtual screening: an endless staircase? Nat. Rev. Drug Disc. ”