Moroz Y. Synthetically accessible chemical space for discovery of new medicines

Українська версія

Thesis for the degree of Doctor of Science (DSc)

State registration number

0524U000317

Thesis Registration Form

0524U000317.pdf

Applicant for

Yurii S. Moroz

Specialization

02.00.03 - Органічна хімія

Date of defense

01-10-2024

Specialized Academic Board

Д 26.001.25

Taras Shevchenko National University of Kyiv

Essay

The thesis is devoted to developing approaches to the creation of synthetically accessible chemical space and to its application in drug discovery. To achieve the goal of the work, methods of one-pot parallel synthesis of classes of small molecules that are often found among known and experimental drugs and biologically active compounds were developed: amides, oxamides, sulfonamides, substituted ureas, secondary amines, alkyl sulfides, sulfoxides and sulfones, semicarbazides, sulfonyl fluorides, and hydantoins, as well as compounds with structural fragments of disubstituted 1,2,4-oxodiazole, 5-dialkylamino-N-alkyltetrazole, 3-amino-1,2,4- triazole, and 1,3,5-trisubstituted 1,2,4 -triazole. We showed that the developed methods allow obtaining compounds fast and with high synthetic success rates thus forming a basis for charting an ultra-large synthetically accessible chemical space. We described this synthetically accessible chemical space of small molecules utilizing the experimental data obtained during the development of parallel synthesis procedures. The results were extrapolated to the in-stock available starting reagents. This made it possible to describe tens of billions of chemically diverse synthetically accessible molecules.

Official opponents

Andrii I. Vovk
Valentyn A. Chebanov
Yurii L. Yahupolskyi

Scientific advisers

Andrii O. Tolmachov

Research papers

Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Pipko, S. E.; Konovets, A. I.; Sadkova, I. V.; Tolmachev, A. Sulfonyl Fluorides as Alternative to Sulfonyl Chlorides in Parallel Synthesis of Aliphatic Sulfonamides. ACS Comb Sci 2014, 16 (4), 192–197.

Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Granat, D. S.; Pipko, S. E.; Konovets, A. I.; Doroschuk, R.; Tolmachev, A. Bis(2,2,2-Trifluoroethyl) Carbonate as a Condensing Agent in One-Pot Parallel Synthesis of Unsymmetrical Aliphatic Ureas. ACS Comb Sci 2014, 16 (6), 303–308.

Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Panov, D. M.; Pipko, S. E.; Konovets, A. I.; Tolmachev, A. A One-Pot Parallel Reductive Amination of Aldehydes with Heteroaromatic Amines. ACS Comb Sci 2014, 16 (8), 375–380.

Bogolubsky, A. V.; Moroz, Y. S.; Pipko, S. E.; Panov, D. M.; Konovets, A. I.; Doroschuk, R.; Tolmachev, A. One-Pot Parallel Synthesis Approach to Secondary Amines Based on the Reductive Amination of Ketones. Synthesis (Germany) 2014, 46 (13), 1765–1772.

Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Ostapchuk, E. N.; Rudnichenko, A. V.; Dmytriv, Y. V.; Bondar, A. N.; Zaporozhets, O. A.; Pipko, S. E.; Doroschuk, R. A.; Babichenko, L. N.; Konovets, A. I.; Tolmachev, A. One-Pot Parallel Synthesis of Alkyl Sulfides, Sulfoxides, and Sulfones. ACS Comb Sci 2015, 17 (6), 348–354.

Bogolyubsky, A. V.; Savych, O.; Zhemera, A. V.; Pipko, S. E.; Grishchenko, A. V.; Konovets, A. I.; Doroshchuk, R. O.; Khomenko, D. N.; Brovarets, V. S.; Moroz, Y. S.; Vybornyi, M. Facile One-Pot Parallel Synthesis of 3-Amino-1,2,4- Triazoles. ACS Comb Sci 2018, 20 (7), 461–466.

Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Pipko, S. E.; Zhemera, A. V.; Konovets, A. I.; Stepaniuk, O. O.; Myronchuk, I. S.; Dmytriv, Y. V.; Doroschuk, R. A.; Zaporozhets, O. A.; Tolmachev, A. 2,2,2-Trifluoroethyl Chlorooxoacetate—Universal Reagent for One-Pot Parallel Synthesis of N 1 -ArylN 2 -Alkyl-Substituted Oxamides. ACS Comb Sci 2015, 17 (10), 615–622.

Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Pipko, S. E.; Grishchenko, A. V.; Zhemera, A. V.; Konovets, A. I.; Doroschuk, R. A.; Dmytriv, Y. V.; Zaporozhets, O. A.; Tolmachev, A. 2,2,2‐Trifluoroethyl Oxalates in the One‐ Pot Parallel Synthesis of Hindered Aliphatic Oxamides. European J Org Chem 2016, 2016 (12), 2120–2130.

Tolmachova, K. A.; Moroz, Y. S.; Konovets, A.; Platonov, M. O.; Vasylchenko, O. V.; Borysko, P.; Zozulya, S.; Gryniukova, A.; Bogolubsky, A. V.; Pipko, S.; Mykhailiuk, P. K.; Brovarets, V. S.; Grygorenko, O. O. (Chlorosulfonyl)Benzenesulfonyl Fluorides—Versatile Building Blocks for Combinatorial Chemistry: Design, Synthesis and Evaluation of a Covalent Inhibitor Library. ACS Comb Sci 2018, 20 (11), 672–680.

Tolmachev, A.; Bogolubsky, A. V.; Pipko, S. E.; Grishchenko, A. V.; Ushakov, D. V.; Zhemera, A. V.; Viniychuk, O. O.; Konovets, A. I.; Zaporozhets, O. A.; Mykhailiuk, P. K.; Moroz, Y. S. Expanding Synthesizable Space of Disubstituted 1,2,4-Oxadiazoles. ACS Comb Sci 2016, 18 (10), 616–624.

Bogolubsky, A. V.; Moroz, Y. S.; Savych, O.; Pipko, S.; Konovets, A.; Platonov, M. O.; Vasylchenko, O. V.; Hurmach, V. V.; Grygorenko, O. O. An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries. ACS Comb Sci 2018, 20 (1), 35–43.

Savych, O.; Kuchkovska, Y. O.; Bogolyubsky, A. V.; Konovets, A. I.; Gubina, K. E.; Pipko, S. E.; Zhemera, A. V.; Grishchenko, A. V.; Khomenko, D. N.; Brovarets, V. S.; Doroschuk, R.; Moroz, Y. S.; Grygorenko, O. O. One-Pot Parallel Synthesis of 5-(Dialkylamino)Tetrazoles. ACS Comb Sci 2019, 21 (9), 635–642.

Grygorenko, O. O.; Radchenko, D. S.; Dziuba, I.; Chuprina, A.; Gubina, K. E.; Moroz, Y. S. Generating Multibillion Chemical Space of Readily Accessible Screening Compounds. iScience 2020, 23 (11), 101681.

Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Dmytriv, Y. V.; Pipko, S. E.; Babichenko, L. N.; Konovets, A. I.; Tolmachev, A. Facile One-Pot Synthesis of 4-Substituted Semicarbazides. RSC Adv 2015, 5 (2), 1063–1069.

Radchenko, D. S.; Naumchyk, V. S.; Dziuba, I.; Kyrylchuk, A. A.; Gubina, K. E.; Moroz, Y. S.; Grygorenko, O. O. One-Pot Parallel Synthesis of 1,3,5- Trisubstituted 1,2,4-Triazoles. Mol Divers 2022, 26 (2), 993–1004.

Irwin, J. J.; Tang, K. G.; Young, J.; Dandarchuluun, C.; Wong, B. R.; Khurelbaatar, M.; Moroz, Y. S.; Mayfield, J.; Sayle, R. A. ZINC20—A Free Ultralarge-Scale Chemical Database for Ligand Discovery. J Chem Inf Model 2020, 60 (12), 6065–6073.

Tingle, B. I.; Tang, K. G.; Castanon, M.; Gutierrez, J. J.; Khurelbaatar, M.; Dandarchuluun, C.; Moroz, Y. S.; Irwin, J. J. ZINC-22─A Free Multi-Billion-Scale Database of Tangible Compounds for Ligand Discovery. J Chem Inf Model 2023, 63 (4), 1166–1176.

Gorgulla, C.; Boeszoermenyi, A.; Wang, Z.-F.; Fischer, P. D.; Coote, P. W.; Padmanabha Das, K. M.; Malets, Y. S.; Radchenko, D. S.; Moroz, Y. S.; Scott, D. A.; Fackeldey, K.; Hoffmann, M.; Iavniuk, I.; Wagner, G.; Arthanari, H. An OpenSource Drug Discovery Platform Enables Ultra-Large Virtual Screens. Nature 2020, 580 (7805), 663–668.

Sadybekov, A. A.; Sadybekov, A. V.; Liu, Y.; Iliopoulos-Tsoutsouvas, C.; Huang, X.-P.; Pickett, J.; Houser, B.; Patel, N.; Tran, N. K.; Tong, F.; Zvonok, N.; Jain, M. K.; Savych, O.; Radchenko, D. S.; Nikas, S. P.; Petasis, N. A.; Moroz, Y. S.; Roth, B. L.; Makriyannis, A.; Katritch, V. Synthon-Based Ligand Discovery in Virtual Libraries of over 11 Billion Compounds. Nature 2022, 601 (7893), 452–459.

Müller, J.; Klein, R.; Tarkhanova, O.; Gryniukova, A.; Borysko, P.; Merkl, S.; Ruf, M.; Neumann, A.; Gastreich, M.; Moroz, Y. S.; Klebe, G.; Glinca, S. Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces. J Med Chem 2022, 65 (23), 15663–15678.

Borysko, P.; Moroz, Y. S.; Vasylchenko, O. V.; Hurmach, V. V.; Starodubtseva, A.; Stefanishena, N.; Nesteruk, K.; Zozulya, S.; Kondratov, I. S.; Grygorenko, O. O. Straightforward Hit Identification Approach in Fragment-Based Discovery of Bromodomain-Containing Protein 4 (BRD4) Inhibitors. Bioorg Med Chem 2018, 26 (12), 3399–3405.

Klingler, F.-M.; Gastreich, M.; Grygorenko, O.; Savych, O.; Borysko, P.; Griniukova, A.; Gubina, K.; Lemmen, C.; Moroz, Y. SAR by Space: Enriching Hit Sets from the Chemical Space. Molecules 2019, 24 (17), 3096.

Chen, Y.; Craven, G. B.; Kamber, R. A.; Cuesta, A.; Zhersh, S.; Moroz, Y. S.; Bassik, M. C.; Taunton, J. Direct Mapping of Ligandable Tyrosines and Lysines in Cells with Chiral Sulfonyl Fluoride Probes. Nat Chem 2023, 15 (11), 1616–1625.

Lyu, J.; Wang, S.; Balius, T. E.; Singh, I.; Levit, A.; Moroz, Y. S.; O’Meara, M. J.; Che, T.; Algaa, E.; Tolmachova, K.; Tolmachev, A. A.; Shoichet, B. K.; Roth, B. L.; Irwin, J. J. Ultra-Large Library Docking for Discovering New Chemotypes. Nature 2019, 566 (7743), 224–229.

Stein, R. M.; Kang, H. J.; McCorvy, J. D.; Glatfelter, G. C.; Jones, A. J.; Che, T.; Slocum, S.; Huang, X.-P.; Savych, O.; Moroz, Y. S.; Stauch, B.; Johansson, L. C.; Cherezov, V.; Kenakin, T.; Irwin, J. J.; Shoichet, B. K.; Roth, B. L.; Dubocovich, M. L. Virtual Discovery of Melatonin Receptor Ligands to Modulate Circadian Rhythms. Nature 2020, 579 (7800), 609–614

Alon, A.; Lyu, J.; Braz, J. M.; Tummino, T. A.; Craik, V.; O’Meara, M. J.; Webb, C. M.; Radchenko, D. S.; Moroz, Y. S.; Huang, X.-P.; Liu, Y.; Roth, B. L.; Irwin, J. J.; Basbaum, A. I.; Shoichet, B. K.; Kruse, A. C. Structures of the σ2 Receptor Enable Docking for Bioactive Ligand Discovery. Nature 2021, 600 (7890), 759–764.

Fink, E. A.; Xu, J.; Hübner, H.; Braz, J. M.; Seemann, P.; Avet, C.; Craik, V.; Weikert, D.; Schmidt, M. F.; Webb, C. M.; Tolmachova, N. A.; Moroz, Y. S.; Huang, X.-P.; Kalyanaraman, C.; Gahbauer, S.; Chen, G.; Liu, Z.; Jacobson, M. P.; Irwin, J. J.; Bouvier, M.; Du, Y.; Shoichet, B. K.; Basbaum, A. I.; Gmeiner, P. Structure-Based Discovery of Nonopioid Analgesics Acting through the α2A - Adrenergic Receptor. Science (1979) 2022, 377 (6614).

Gahbauer, S.; DeLeon, C.; Braz, J. M.; Craik, V.; Kang, H. J.; Wan, X.; Huang, X.-P.; Billesbølle, C. B.; Liu, Y.; Che, T.; Deshpande, I.; Jewell, M.; Fink, E. A.; Kondratov, I. S.; Moroz, Y. S.; Irwin, J. J.; Basbaum, A. I.; Roth, B. L.; Shoichet, B. K. Docking for EP4R Antagonists Active against Inflammatory Pain. Nat Commun 2023, 14 (1), 8067.

Gorgulla, C.; Padmanabha Das, K. M.; Leigh, K. E.; Cespugli, M.; Fischer, P. D.; Wang, Z.-F.; Tesseyre, G.; Pandita, S.; Shnapir, A.; Calderaio, A.; Gechev, M.; Rose, A.; Lewis, N.; Hutcheson, C.; Yaffe, E.; Luxenburg, R.; Herce, H. D.; Durmaz, V.; Halazonetis, T. D.; Fackeldey, K.; Patten, J. J.; Chuprina, A.; Dziuba, I.; Plekhova, A.; Moroz, Y.; Radchenko, D.; Tarkhanova, O.; Yavnyuk, I.; Gruber, C.; Yust, R.; Payne, D.; Näär, A. M.; Namchuk, M. N.; Davey, R. A.; Wagner, G.; Kinney, J.; Arthanari, H. A Multi-Pronged Approach Targeting SARS-CoV-2 Proteins Using Ultra-Large Virtual Screening. iScience 2021, 24 (2), 102021.

Gahbauer, S.; Correy, G. J.; Schuller, M.; Ferla, M. P.; Doruk, Y. U.; Rachman, M.; Wu, T.; Diolaiti, M.; Wang, S.; Neitz, R. J.; Fearon, D.; Radchenko, D. S.; Moroz, Y. S.; Irwin, J. J.; Renslo, A. R.; Taylor, J. C.; Gestwicki, J. E.; von Delft, F.; Ashworth, A.; Ahel, I.; Shoichet, B. K.; Fraser, J. S. Iterative Computational Design and Crystallographic Screening Identifies Potent Inhibitors Targeting the Nsp3 Macrodomain of SARS-CoV-2. Proceedings of the National Academy of Sciences 2023, 120 (2). 2212931120.

Singh, I.; Li, F.; Fink, E. A.; Chau, I.; Li, A.; Rodriguez-Hernández, A.; Glenn, I.; Zapatero-Belinchón, F. J.; Rodriguez, M. L.; Devkota, K.; Deng, Z.; White, K.; Wan, X.; Tolmachova, N. A.; Moroz, Y. S.; Kaniskan, H. Ü.; Ott, M.; García-Sastre, A.; Jin, J.; Fujimori, D. G.; Irwin, J. J.; Vedadi, M.; Shoichet, B. K. Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7- Methyltransferase. J Med Chem 2023, 66 (12), 7785–7803.

Fink, E. A.; Bardine, C.; Gahbauer, S.; Singh, I.; Detomasi, T. C.; White, K.; Gu, S.; Wan, X.; Chen, J.; Ary, B.; Glenn, I.; O’Connell, J.; O’Donnell, H.; Fajtová, P.; Lyu, J.; Vigneron, S.; Young, N. J.; Kondratov, I. S.; Alisoltani, A.; Simons, L. M.; Lorenzo‐Redondo, R.; Ozer, E. A.; Hultquist, J. F.; O’Donoghue, A. J.; Moroz, Y. S.; Taunton, J.; Renslo, A. R.; Irwin, J. J.; García‐Sastre, A.; Shoichet, B. K.; Craik, C. S. Large Library Docking for Novel SARS‐CoV‐2 Main Protease Non‐ covalent and Covalent Inhibitors. Protein Science 2023, 32 (8), 4712.

Yarish, D.; Garkot, S.; Grygorenko, O. O.; Radchenko, D. S.; Moroz, Y. S.; Gurbych, O. Advancing Molecular Graphs with Descriptors for the Prediction of Chemical Reaction Yields. J Comput Chem 2023, 44 (2), 76–92.

Liu, Z.; Moroz, Y. S.; Isayev, O. The Challenge of Balancing Model Sensitivity and Robustness in Predicting Yields: A Benchmarking Study of Amide Coupling Reactions. Chem Sci 2023, 14 (39), 10835–10846.

Korshunova, M.; Huang, N.; Capuzzi, S.; Radchenko, D. S.; Savych, O.; Moroz, Y. S.; Wells, C. I.; Willson, T. M.; Tropsha, A.; Isayev, O. Generative and Reinforcement Learning Approaches for the Automated de Novo Design of Bioactive Compounds. Commun Chem 2022, 5 (1), 129.

Gryniukova, A.; Kaiser, F.; Myziuk, I.; Alieksieieva, D.; Leberecht, C.; Heym, P. P.; Tarkhanova, O. O.; Moroz, Y. S.; Borysko, P.; Haupt, V. J. AIPowered Virtual Screening of Large Compound Libraries Leads to the Discovery of Novel Inhibitors of Sirtuin-1. J Med Chem 2023, 66 (15), 10241–10251.

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