Rapidly discovering new compounds for Zika virus
As part of an ambitious European project, Exscalate’s supercomputing platform was leveraged to support the scientific community in successfully identifying active compounds against Zika virus in a very limited timescale.
Zika virus represents a huge unmet medical need as there is no specific treatment available for it or its associated diseases. Belonging to the genus Falivirus, Zika virus is primarily transmitted by the bite of an infected mosquito in tropical and subtropical regions. The symptoms of Zika virus infection are usually mild, including fever, rash, conjunctivitis, muscle and joint pain, malaise or headache. However, complications arise during pregnancy as the infection can spread from the mother to the fetus causing severe defects when the baby is born, such as microcephaly and other congenital malformations and developmental problems. There is also an increased risk of neurologic complications associated with Zika virus infection in adults and children.
It is little surprise then that the rapid spread of Zika virus from south America to north America as well as islands in the Pacific and southeast Asia in 2016 was a cause of much concern. The World Health Organization actually declared Zika a pandemic issue.
The ANTAREX4ZIKA research project, funded under the HPC (High Performance Computing) H2020 Future and Emerging Technologies program, was set up by Exscalate to address this unmet medical need. The objective was to identify both repurposing and de novo inhibitors for Zika. Bringing together supercomputing resources including CINECA, the Italian Supercomputing center, and IT4Innovations, the Czech Supercomputing Tier-1 center, as well as scientific research and academic institutions, such as Politecnico di Milano, the project would covering all phases of drug discovery, from hit to candidate.
For this project, Exscalate used its simulation software LiGen, which had been specifically designed and developed for high performance computing, to screen the in silico poly-pharmacological profile of Zika (7 Zika proteins, 9 conformations, 13 binding sites).
To carry out the simulation, Exscalate created a virtual chemical space of 1.2 billion ligands (including all drugs on the market and those under study). Thanks to the power of the Marconi supercomputer at CINECA, this database of 1.2 billion ligands was screened, representing the largest virtual screening experiment performed at that time in terms of processing threads (up to one million) and compound database size (one billion molecules).
The repurposing approach identified Dactosinib as an active compound. A positive proof-of-concept in the animal models was achieved in just three months from the start of screenings. Activities on de novo chemical compounds also identified a new class of compounds. Two in vitro active compounds have been taken forward to be further characterized in a conventional drug development process.
ANTAREX4Zika partners intend to make the project’s simulation results available to the scientific community in order to support and accelerate the discovery of a novel treatment to fight the Zika pandemic.
For Exscalate, partnering in this project, which represented the first validation of the Exscalate platform, proved how leveraging HPC technologies can optimize molecular docking. This helped reduce the virtual screening process for the identification of new compounds by two orders of magnitude.
The result is an accelerated drug discovery process that offers many possibilities for the scientific community in how the platform can be used to reduce the time between the discovery of a health threat, such as the sudden appearance of a pandemic virus, to the prompt availability of candidate drugs.