Lead optimization

In less than a year, the COVID Moonshot open science collaboration developed a novel non-peptidomimetic small molecule orally bioavailable SARS-CoV-2 main viral protease (Mpro) inhibitor with potent antiviral activity starting from a high-throughput fragment screen. To achieve this, rapid cycles of medicinal chemistry were performed, directed by a team composed of industry veterans with over 100 years of accumulated industry experience. The team leveraged Al-driven synthesis planning for rapidly sourcing molecules from CROs, high-throughput co-crystallisation data generated with just 1 week turnaround, and the world's largest computing network to perform hundreds of thousands of alchemical free energy calculations. About 2000 compounds were synthesized and assayed, and more than 450 X-ray structures solved in the process, generating rich structure-activity and property relationships for multiple lead series with distinct chemotypes. With a SARS-CoV-2 specific Mpro inhibitor now progressing to IND-enabling studies, the COVID Moonshot aims to harness the infrastructure it has built for pandemic preparedness. Our Lead Optimization proposal (Project 5) for the ASAP Center is to progress six early lead compounds developed by Project 3 and 4, towards readiness for preclinical development (Project 6). We anticipate that up to three preclinical packages will be developed within the Center, and three made available externally. Within Project 5, we will enhance and scale up existing lead optimization processes, building on the resources and collaborator network that rapidly produced and progressed the COVID Moonshot SARS-CoV-2 Mpro inhibitor en route to the clinic. Further, we will harness the knowledge and expertise of our new collaborators, lending cellular assays and antiviral models that are required to develop new direct acting antivirals for coronaviridae, flaviviridae and picornaviridae (Project 1 and antiviral core). In addition, we will develop our technology base: the co-location of integrated, tiered in vitro - in vivo ADMET screening cascades with our synthesis partners will increase efficiency, and exploiting cloud based material logistics and activity databases will optimize shipment and data logistics. We will work in a fully open-science model, to ensure resulting therapies can be produced at cost by manufacturers world-wide and secure long term availability for future pandemics whenever they arise. In addition to molecules that will be developed for pandemic preparedness and ultimate patient benefit, the integrated lead optimization datasets, with linked ADMET, protein-ligand structures underpinning designed compounds, synthesis routes, and antiviral assay, are anticipated to become a vital resource in the improvement of oral direct acting antiviral discovery as well as a foundational teaching resource.