Using high-performance computing, researchers have demonstrated a breakthrough approach that scales up and accelerates the discovery of novel drugs.
Drug development is a lengthy process. From the time a health threat is discovered, it takes years until an effective drug is available on the market. During all this time the disease-spreading virus doesn’t kindly wait around for the drug industry to catch up, but instead continues to wreak havoc on people’s health. However, a breakthrough approach conceived by a team of researchers working on the ANTAREX project promises to help shorten the path from the discovery of a health threat to the availability of a cure.
The team’s approach is based on exascale-ready high-performance computing that they’ve applied to accelerating drug discovery. Using a 10 petaflop Marconi Intel Xeon Phi supercomputer – ranked the 19th most powerful computer in the world on the November 2018 TOP500 list – the ANTAREX partners focused on the real-life case of the Zika pandemic crisis.
Zika virus at a glance
It’s only in recent years that the Zika virus has made global headlines. The 2015 outbreak in Brazil, which quickly spread to other parts of South and North America, as well as other regions worldwide, prompted the World Health Organization to declare it a public health emergency. However, the virus has been around for much longer. In fact, its first recorded appearance was in 1947 in Uganda’s tropical Zika forest, from where it gets its name. Spread mainly by the yellow fever and tiger mosquitos, the virus can result in neurological complications such as the Guillain-Barré syndrome, neuropathy and myelitis in adults and children. Infected pregnant women run the risk of giving birth to babies with severe defects like microcephaly.
In the Zika case study, the ANTAREX team identified 26 binding sites from the crystal structures of 5 Zika proteins: NS5, NS1, NS2B/NS3, NS3 and the envelope protein. A total of 1.2 billion molecules were tested via computer simulation on 1 million computational threads available through the Marconi supercomputer. This makes it the largest virtual screening experiment ever launched in terms of computational threads and compound database size.
Advanced tool in drug discovery
The focus of the experiment was on molecular docking, an increasingly important tool for drug discovery. The team identified the most druggable site on Zika’s proteome. Ultra-fast molecular docking was performed in parallel on all binding sites and the best conformation was identified on each site. The best molecule identified in the experiment is predicted to bind and potentially inhibit three out of seven Zika protein domains ranked on their multitarget activity: the NS5 polymerase and methyltransferase sites and the NS3 elicase site.
Accelerated screening for the drug discovery process is now possible, according to Prof. Christina Silvano, project coordinator of Politecnico di Milano. “[G]eometrical docking was accelerated by two orders of magnitude with respect to other solutions available on the market,” she said in an interview conducted at the High Performance and Embedded Architecture and Compilation conference earlier this year. “That was a very important success for our application and we think this is very important also for the society.”
ANTAREX (AutoTuning and Adaptivity appRoach for Energy efficient eXascale HPC systems) also focused on a second scenario involving the mitigation of traffic congestion in smart cities using a self-adaptive navigation system. The project ended in November 2018.