Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.
Melissa L BobyDaren FearonMatteo FerlaMihajlo FilepLizbé KoekemoerMatthew C Robinsonnull nullJohn D ChoderaAlpha A LeeNir LondonAnnette von DelftFrank von DelftHagit AchdoutAnthony AimonDominic S AlonziRobert ArbonJasmin C AschenbrennerBlake H BalcombElad Bar-DavidHaim BarrAmir Ben-ShmuelJames BennettVitaliy A BilenkoBruce BordenPascale BouletGregory R BowmanLennart BrewitzJuliane BrunSarma BvnbsMark CalmianoAnna CarberyDaniel W CarneyEmma CattermoleEdcon ChangEugene ChernyshenkoAustin ClydeJoseph E CofflandGalit CohenJason C ColeAlessandro ContiniLisa CoxTristan Ian CrollMilan CvitkovicSteven De JongheAlex DiasKim DonckersDavid L DotsonAlice DouangamathShirly DubersteinTim DudgeonLouise E DunnettPeter EastmanNoam ErezCharles J EyermannMichael FairheadGwen FateOleg FedorovRafaela S FernandesLori FerrinsRichard FosterHolly FosterLaurent FraisseRonen GabizonAdolfo García-SastreVictor O GawriljukPaul GehrtzCarina GileadiCharline GiroudWilliam G GlassRobert C GlenItai GlinertAndre S GodoyMarian GorichkoTyler Gorrie-StoneEd J GriffenAmna HaneefStorm Hassell HartJag HeerMichael HenryMichelle HillSam HorrellQiu Yu Judy HuangVictor D HuliakMatthew F D HurleyTomer IsraelyAndrew JajackJitske JansenEric JnoffDirk JochmansTobias JohnBenjamin KaminowLulu KangAnastassia L KantsadiPeter W KennyJ L KiappesSerhii O KinakhBoris KovarTobias KrojerVan Ngoc Thuy LaSophie Laghnimi-HahnBruce A LefkerHaim LevyRyan M LithgoIvan G LogvinenkoPetra LukacikHannah Bruce MacdonaldElizabeth M MacLeanLaetitia L MakowerTika R MallaPeter G MarplesTatiana MatviiukWillam McCorkindaleBriana L McGovernSharon MelamedKostiantyn P MelnykovOleg MichurinPascal MiesenHalina MikolajekBruce F MilneDavid MinhAaron MorrisGarrett M MorrisMelody Jane MorwitzerDemetri MoustakasCharles E MowbrayAline M NakamuraJose Brandao NetoJohan NeytsLuong NguyenGabriela D NoskeVladas OleinikovasGlaucius OlivaGijs J OverheulC David OwenRuby PaiJin PanNir ParanAlexander Matthew PayneBenjamin PerryManeesh PingleJakir PinjariBoaz PolitiAilsa PowellVladimír PšenákIván PulidoReut PuniVictor L RangelRambabu N ReddiPaul ReesSt Patrick ReidLauren ReidEfrat ResnickEmily Grace RipkaRalph P RobinsonJaime Rodriguez-GuerraRomel RosalesDominic A RufaKadi SaarKumar Singh SaikatenduEidarus SalahDavid SchallerJenke ScheenCelia A SchifferChristopher J SchofieldMikhail ShafeevAarif ShaikhAla M ShaqraJiye ShiKhriesto ShurrushSukrit SinghAssa SittnerPeter SjöRachael SkynerAdam SmalleyBart SmeetsMihaela D SmilovaLeonardo J SolmeskyJohn SpencerClaire Strain-DamerellVishwanath SwamyHadas TamirJenny C TaylorRachael E TennantWarren ThompsonAndrew ThompsonSusana TomásioCharles W E TomlinsonIgor S TsurupaAnthony TumberIoannis VakonakisRonald P van RijLaura VangeelFinny S VargheseMariana VaschettoEinat B VitnerVincent VoelzAndrea VolkamerMartin A WalshWalter WardCharlie WeatherallShay WeissKris M WhiteConor Francis WildKarolina D WittMatthew WittmannNathan WrightYfat Yahalom-RonenNese Kurt YilmazDaniel ZaidmannIvy ZhangHadeer ZidaneNicole ZitzmannSarah N ZvornicaninPublished in: Science (New York, N.Y.) (2023)
We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.