Ligand-based discovery of coronavirus main protease inhibitors using MACAW molecular embeddings

References

• Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20(5):533–534.
   PubMed Web of Science ®Google Scholar
• Selickman J, Vrettou CS, Mentzelopoulos SD, Marini JJ. COVID-19-related ARDS: key mechanistic features and treatments. J Clin Med. 2022;11(16):4896.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Geng X, Tan Y, Li Q, XuC, XuJ, Hao L, Zeng Z, Luo X, Liu F, et al. New understanding of the damage of SARS-CoV-2 infection outside the respiratory system. Biomed Pharmacother. 2020;127:110195.
   PubMed Web of Science ®Google Scholar
• Fazzini B, Battaglini D, Carenzo L, Pelosi P, Cecconi M, Puthucheary Z. Physical and psychological impairment in survivors of acute respiratory distress syndrome: a systematic review and meta-analysis. Br J Anaesthesia. 2022:S0007-0912(22)00455-X.
   Web of Science ®Google Scholar
• Munipalli B, Seim L, Dawson NL, Knight D, Dabrh AMA. Post-acute sequelae of COVID-19 (PASC): a meta-narrative review of pathophysiology, prevalence, and management. SN Compr Clin Med. 2022;4(1):90.
   PubMedGoogle Scholar
• Delshad M, Sanaei M-J, Pourbagheri-Sigaroodi A, Bashash D. Host genetic diversity and genetic variations of SARS-CoV-2 in COVID-19 pathogenesis and the effectiveness of vaccination. Int Immunopharmacol. 2022;111:109128.
   PubMed Web of Science ®Google Scholar
• Chen Q, Zhang J, Wang P, Zhang Z. The mechanisms of immune response and evasion by the main SARS-CoV-2 variants. iScience. 2022;25(10):105044.
   PubMed Web of Science ®Google Scholar
• Gil C, Ginex T, Maestro I, Nozal V, Barrado-Gil L, Cuesta-Geijo MÁ, Urquiza J, Ramírez D, Alonso C, Campillo NE, et al. COVID-19: drug targets and potential treatments. J Med Chem. 2020;63(21):12359–12386.
   PubMed Web of Science ®Google Scholar
• LiS, LiS, Disoma C, Zheng R, Zhou M, Razzaq A, Liu P, Zhou Y, Dong Z, Du A, et al. SARS-CoV-2: mechanism of infection and emerging technologies for future prospects. Rev Med Virol. 2021;31(2):e2168.
   PubMed Web of Science ®Google Scholar
• Jamison DA, Anand Narayanan S, Trovão NS, Guarnieri JW, Topper MJ, Moraes-Vieira PM, Zaksas V, Singh KK, Wurtele ES, Beheshti A. A comprehensive SARS-CoV-2 and COVID-19 review, part 1: intracellular overdrive for SARS-CoV-2 infection. Eur J Hum Genet. 2022;30(8):889–898.
   PubMed Web of Science ®Google Scholar
• Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol. 2022;23(1):3–20.
   PubMed Web of Science ®Google Scholar
• V’kovskiP, KratzelA, SteinerS, StalderH, ThielV. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. 2021;19(3):155–170.
   PubMed Web of Science ®Google Scholar
• Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19(3):141–154.
   PubMed Web of Science ®Google Scholar
• Chan JF-W, Kok K-H, Zhu Z, Chu H, To KK-W, Yuan S, Yuen K-Y. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect. 2020;9(1):221–236.
   PubMed Web of Science ®Google Scholar
• Chia CSB, Xu W, Shuyi Ng P. A patent review on SARS coronavirus main protease (3CLpro) inhibitors. ChemMedChem. 2022;17(1):e202100576.
   PubMed Web of Science ®Google Scholar
• Vangeel L, Chiu W, De Jonghe S, Maes P, Slechten B, Raymenants J, André E, Leyssen P, Neyts J, Jochmans D. Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022;198:105252.
   PubMed Web of Science ®Google Scholar
• SiemieniukRA, BartoszkoJJ, ZeraatkarD, KumE, QasimA, MartinezJPD, IzcovichA, LamontagneF, HanMA, AgarwalA, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ. 2020;370:m2980.
   PubMed Web of Science ®Google Scholar
• Zhou S, Hill CS, Sarkar S, Tse LV, Woodburn BMD, Schinazi RF, Sheahan TP, Baric RS, Heise MT, Swanstrom R. β-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells. J Infect Dis. 2021;224(3):415–419.
   PubMed Web of Science ®Google Scholar
• Fischer WA, Eron JJ, Holman W, Cohen MS, Fang L, Szewczyk LJ, Sheahan TP, Baric R, Mollan KR, Wolfe CR, et al. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med. 2022;14(628):eabl7430.
   PubMed Web of Science ®Google Scholar
• Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, Boras B, Cardin RD, Carlo A, Coffman KJ, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science. 2021;374 (6575):eabl4784–1593.
   Web of Science ®Google Scholar
• BorasB, JonesRM, AnsonBJ, ArensonD, AschenbrennerL, BakowskiMA, BeutlerN, BinderJ, ChenE, EngH, et al. Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. Nat Commun. 2021;12(1):6055.
   PubMed Web of Science ®Google Scholar
• Wanounou M, Caraco Y, Levy RH, Bialer M, Perucca E. Clinically relevant interactions between ritonavir-boosted nirmatrelvir and concomitant antiseizure medications: implications for the management of COVID-19 in patients with epilepsy. Clin Pharmacokinet. 2022;61(9):1219–1236.
   PubMed Web of Science ®Google Scholar
• Yang KS, Leeuwon SZ, Xu S, Liu WR. Evolutionary and structural insights about potential SARS-CoV-2 evasion of nirmatrelvir. J Med Chem. 2022;65(13):8686–8698.
   PubMedGoogle Scholar
• Narayanan D, Parimon T. Current therapeutics for COVID-19, what we know about the molecular mechanism and efficacy of treatments for this novel virus. IJMS. 2022;23(14):7702.
   Google Scholar
• Md Khairi LNH, Fahrni ML, Lazzarino AI. The race for global equitable access to COVID-19 vaccines. Vaccines. 2022;10(8):1306.
   Web of Science ®Google Scholar
• Hegyi A, Ziebuhr J. Conservation of substrate specificities among coronavirus main proteases. J Gen Virol. 2002;83(Pt 3):595–599.
   PubMedGoogle Scholar
• Drayman N, DeMarco JK, Jones KA, Azizi S-A, Froggatt HM, Tan K, Maltseva NI, Chen S, Nicolaescu V, Dvorkin S, et al. Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2. Science. 2021;373(6557):931–936.
   PubMed Web of Science ®Google Scholar
• Liu H, Iketani S, Zask A, Khanizeman N, Bednarova E, Forouhar F, Fowler B, Hong SJ, Mohri H, Nair MS, et al. Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19. Nat Commun. 2022;13(1):1891.
   PubMed Web of Science ®Google Scholar
• Xiu S, Dick A, Ju H, Mirzaie S, Abdi F, Cocklin S, Zhan P, Liu X. Inhibitors of SARS-CoV-2 entry: current and future opportunities. J Med Chem. 2020;63(21):12256–12274.
   PubMed Web of Science ®Google Scholar
• Yan F, Gao F. An overview of potential inhibitors targeting non-structural proteins 3 (PLpro and Mac1) and 5 (3CLpro/Mpro) of SARS-CoV-2. Comput Struct Biotechnol J. 2021;19:4868–4883.
   PubMed Web of Science ®Google Scholar
• Pavan M, Bassani D, Sturlese M, Moro S. Bat coronaviruses related to SARS-CoV-2: What about their 3CL proteases (MPro)?J Enzyme Inhib Med Chem. 2022;37(1):1077–1082.
   PubMed Web of Science ®Google Scholar
• Clyde A, Galanie S, Kneller DW, Ma H, Babuji Y, Blaiszik B, Brace A, Brettin T, Chard K, Chard R, et al. High-throughput virtual screening and validation of a SARS-CoV-2 main protease noncovalent inhibitor. J Chem Inf Model. 2022;62(1):116–128.
   PubMed Web of Science ®Google Scholar
• Gajjar ND, Dhameliya TM, Shah GB. In search of RdRp and Mpro inhibitors against SARS CoV-2: molecular docking, molecular dynamic simulations and ADMET analysis. J Mol Struct. 2021;1239:130488.
   PubMed Web of Science ®Google Scholar
• Galvez-Llompart M, Zanni R, Galvez J, Basak SC, Goyal SM. COVID-19 and the importance of being prepared: a multidisciplinary strategy for the discovery of antivirals to combat pandemics. Biomedicines. 2022;10(6):1342.
   PubMed Web of Science ®Google Scholar
• Hosseini M, Chen W, Xiao D, Wang C. Computational molecular docking and virtual screening revealed promising SARS-CoV-2 drugs. Precis Clin Med. 2021;4(1):1–16.
   PubMedGoogle Scholar
• Mercorelli B, Desantis J, Celegato M, Bazzacco A, Siragusa L, Benedetti P, Eleuteri M, Croci F, Cruciani G, Goracci L, et al. Discovery of novel SARS-CoV-2 inhibitors targeting the main protease Mpro by virtual screenings and hit optimization. Antiviral Res. 2022;204:105350.
   PubMed Web of Science ®Google Scholar
• Mishra B, Ballaney P, Saha G, Shinde A, Banerjee S, Thimmakondu VS, Aduri R. An in silico discovery of potential 3CL protease inhibitors of SARS-CoV-2 based upon inactivation of the cysteine 145-Histidine 41 catalytic dyad. J Biomol Struct Dyn. 2022;0(0):1–20.
   Google Scholar
• Rao P, Shukla A, Parmar P, Rawal RM, Patel BV, Saraf M, Goswami D. Proposing a fungal metabolite-flaviolin as a potential inhibitor of 3CLpro of novel coronavirus SARS-CoV-2 identified using docking and molecular dynamics. J Biomol Struct Dyn. 2022;40(1):348–360.
   PubMed Web of Science ®Google Scholar
• Sobhia ME, Ghosh K, Sivangula S, Kumar S, Singh H. Identification of potential SARS-CoV-2 Mpro inhibitors integrating molecular docking and water thermodynamics. J Biomol Struct Dyn. 2022;40(11):5079–5089.
   PubMed Web of Science ®Google Scholar
• Zev S, Raz K, Schwartz R, Tarabeh R, Gupta PK, Major DT. Benchmarking the ability of common docking programs to correctly reproduce and score binding modes in SARS-CoV-2 protease Mpro. J Chem Inf Model. 2021;61(6):2957–2966.
   PubMed Web of Science ®Google Scholar
• Cui W, Yang K, Yang H. Recent progress in the drug development targeting SARS-CoV-2 main protease as treatment for COVID-19. Front Mol Biosci. 2020;7:616341.
   PubMed Web of Science ®Google Scholar
• Mengist HM, Dilnessa T, Jin T. Structural basis of potential inhibitors targeting SARS-CoV-2 main protease. Front Chem. 2021;9:622898.
   PubMed Web of Science ®Google Scholar
• Yang H, Yang J. A review of the latest research on Mpro targeting SARS-COV inhibitors. RSC Med Chem. 2021;12:1026–1036.
   PubMedGoogle Scholar
• Blay V, Radivojevic T, Allen JE, Hudson CM, Garcia Martin H. MACAW: an accessible tool for molecular embedding and inverse molecular design. J Chem Inf Model. 2022;62(15):3551–3564.
   PubMed Web of Science ®Google Scholar
• Gao K, Nguyen DD, Chen J, Wang R, Wei G-W. Repositioning of 8565 existing drugs for COVID-19. J Phys Chem Lett. 2020;11(13):5373–5382.
   PubMed Web of Science ®Google Scholar
• Zhu W, Xu M, Chen CZ, Guo H, Shen M, HuX, Shinn P, Klumpp-Thomas C, Michael SG, Zheng W. Identification of SARS-CoV-2 3CL protease inhibitors by a quantitative high-throughput screening. ACS Pharmacol Transl Sci. 2020;3(5):1008–1016.
   PubMedGoogle Scholar
• Kuzikov M, Costanzi E, Reinshagen J, Esposito F, Vangeel L, Wolf M, Ellinger B, Claussen C, Geisslinger G, Corona A, et al. Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in vitro repurposing screen. ACS Pharmacol Transl Sci. 2021;4(3):1096–1110.
   PubMedGoogle Scholar
• Vatansever EC, YangKS, DrelichAK, KratchKC, Cho C-C, KempaiahKR, Hsu JC, Mellott DM, Xu S, Tseng C-TK, et al. Bepridil is potent against SARS-CoV-2 in vitro. Proc Natl Acad Sci USA. 2021;118(10):e2012201118.
   PubMed Web of Science ®Google Scholar
• PostEra. 2021. MPro Activity Data [Internet]. https://covid.postera.ai/covid/activity_data.
   Google Scholar
• Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074–D1082.
   PubMed Web of Science ®Google Scholar
• Pedregosa F, et al. Scikit-learn: machine learning in Python. JMLR. 2011;12:2825–2830.
   Web of Science ®Google Scholar
• Xiong G, WuZ, Yi J, Fu L, Yang Z, Hsieh C, Yin M, Zeng X, WuC, Lu A, et al. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res. 2021;49(W1):W5–W14.
   PubMed Web of Science ®Google Scholar
• Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7(1):42717.
   PubMed Web of Science ®Google Scholar
• Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582(7811):289–293.
   PubMed Web of Science ®Google Scholar
• Amporndanai K, Meng X, Shang W, Jin Z, Rogers M, Zhao Y, Rao Z, Liu Z-J, Yang H, Zhang L, et al. Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives. Nat Commun. 2021;12(1):3061.
   PubMed Web of Science ®Google Scholar
• Reed LJ, Muench H. A simple method of estimating fifty per cent ENDPOINTS12. Am J Epidemiol. 1938;27(3):493–497.
   Google Scholar
• Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1–2):55–63.
   PubMed Web of Science ®Google Scholar
• Silvestrini L, Belhaj N, Comez L, Gerelli Y, Lauria A, Libera V, Mariani P, Marzullo P, Ortore MG, Palumbo Piccionello A, et al. The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors. Sci Rep. 2021;11(1):9283.
   PubMed Web of Science ®Google Scholar
• Ma C, Hu Y, Townsend JA, Lagarias PI, Marty MT, Kolocouris A, Wang J. Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin are nonspecific promiscuous SARS-CoV-2 main protease inhibitors. ACS Pharmacol Transl Sci. 2020;3(6):1265–1277.
   PubMedGoogle Scholar
• Baddock H, Brolih S, Yosaatmadja Y, Ratnaweera M, Bielinski M, Swift L, Cruz-Migoni A, Morris G, Schofield C, Gileadi O, et al. 2020. Characterisation of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification. bioRxiv. https://ora.ox.ac.uk/objects/uuid:3899d504-d33f-4e5c-8cec-588fc841b784.
   Google Scholar
• Bickerton GR, Paolini GV, Besnard J, Muresan S, Hopkins AL. Quantifying the chemical beauty of drugs. Nat Chem. 2012;4(2):90–98.
   PubMed Web of Science ®Google Scholar
• Nepali K, Lee H-Y, Liou J-P. Nitro-group-containing drugs. J Med Chem. 2019;62(6):2851–2893.
   PubMed Web of Science ®Google Scholar
• Stokes JM, Yang K, Swanson K, Jin W, Cubillos-Ruiz A, Donghia NM, MacNair CR, French S, Carfrae LA, Bloom-Ackermann Z, et al. A deep learning approach to antibiotic discovery. Cell. 2020;180(4):688–702.e13.
   PubMed Web of Science ®Google Scholar
• Kladnik J, Dolinar A, Kljun J, Perea D, Grau-Expósito J, Genescà M, Novinec M, Buzon MJ, Turel I. Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication. J Enzyme Inhib Med Chem. 2022;37(1):2158–2168.
   PubMed Web of Science ®Google Scholar
• Poupaert J, Carato P, Colacino E, Yous S. 2(3H)-benzoxazolone and bioisosters as “privileged scaffold” in the design of pharmacological probes. Curr Med Chem. 2005;12(7):877–885.
   PubMed Web of Science ®Google Scholar
• Qiao J, Li Y-S, Zeng R, Liu F-L, Luo R-H, Huang C, Wang Y-F, Zhang J, Quan B, Shen C, et al. SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model. Science. 2021;371(6536):1374–1378.
   PubMed Web of Science ®Google Scholar
• Menéndez CA, Byléhn F, Perez-Lemus GR, Alvarado W, de Pablo JJ. Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease. Sci Adv. 2020;6(37):eabd0345.
   PubMed Web of Science ®Google Scholar
• Samrat SK, Xu J, Xie X, Gianti E, Chen H, Zou J, Pattis JG, Elokely K, Lee H, Li Z, et al. Allosteric inhibitors of the main protease of SARS-CoV-2. Antiviral Res. 2022;205:105381.
   PubMed Web of Science ®Google Scholar
• Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci USA. 2001;98(18):10037–10041.
   PubMed Web of Science ®Google Scholar