How to Discover Antiviral Drugs Quickly (N Engl J Med. 2020.05.20)

We urgently need effective drugs for coronavirus disease 2019 (Covid-19), but what is the quickest way to find them? One approach that sometimes seems akin to a "Hail Mary" pass in American football is to hope that drugs that have worked against a different virus (such as hepatitis C or Ebola) will also work against Covid-19. Alternatively, we can be rational and specifically target proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) so as to interrupt its life cycle.

The SARS-CoV-2 genome encodes approximately 25 proteins that are needed by the virus to infect humans and to replicate (Figure 1). Among these are the notorious spike (S) protein, which recognizes human angiotensin-converting enzyme 2 in the initial stage of infection; two proteases, which cleave viral and human proteins; the RNA polymerase, which synthesizes viral RNA; and the RNA-cleaving endoribonuclease. Finding drugs that can bind to the viral proteins and stop them from working is a logical way forward and the priority of many research laboratories....

....Modern supercomputers such as the Summit supercomputer at Oak Ridge National Laboratory, which is currently the world's most powerful, perform massively parallel processing in which many calculations are performed at the same time. This enables molecular-dynamics simulations of many replicas of the target to be run in parallel, each exploring a slightly different conformational space. Thus, a comprehensive simulation model of a SARS-CoV-2 protein drug target can be obtained with the use of Summit in a day, whereas it would take months with the use of a typical computer cluster. Supercomputers are also used in rapid parallel docking of large databases of compounds. The structure-based drug-discovery field is thus primed for quick results.

So, what is happening now? The laborious, decade-long, classic pathway for the discovery and approval of new drugs could hardly be less well suited to the present pandemic. Repurposing existing drugs offers a potentially rapid mechanism to deployment, since the safety profiles are known. Therefore, a preliminary report of a supercomputer-driven ensemble docking study of a repurposing compound database to the viral S protein was published on a preprint server in mid-February, with 8000 compounds ranked according to the calculated binding affinity to the receptor-binding domain of the S protein.3 Top-ranked compounds from the original S-protein virtual screen are being tested for activity against the live virus. The results will inform future calculations in a speedy, iterative process.

However, in the surreal, accelerated world of Covid-19 research, advances are quickly out of date. Many new experimental three-dimensional structures of the S protein and other viral targets are being reported in quick succession, a process that requires the simulations and docking to be refined and repeated. Artificial intelligence is being used to predict drug binding. Different types of experimental laboratory screening programs have been set up all over the world and are ramping up. Meanwhile, for several SARS-CoV-2 proteins, the virtual high-throughput screening and ensemble docking pipeline is in full production mode, both on supercomputers and with the use of vast cloud-computing resources. None of this guarantees success within any given time frame, but a combination of rationality, scientific insight, and ingenuity with the most powerful tools available will give us our best shot.

抗ウイルス薬を早く発見する方法 (N Engl J Med. 2020.05.20)

新型コロナウイルス感染症 2019(Covid-19)に有効な薬が緊急に必要だが、それを見つけるための最も手っ取り早い方法は何だろうか?時にアメリカンフットボールの「神頼み」パスに似ていると思われる1つのアプローチは、別のウイルス(C型肝炎やエボラなど)に対して効いた薬がCovid-19に対しても効くことを期待することである。あるいは、我々は、合理的に、重症急性呼吸器症候群コロナウイルス2(SARS-CoV-2)のライフサイクルを中断するために、そのウイルスのタンパク質を特異的に標的とするとも可能である。





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