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Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.

Soumana DI, Kurt Yilmaz N, Prachanronarong KL, Aydin C, Ali A, Schiffer CA
ACS Chem Biol 11 900-9 (2016)
Related entries: 5epn, 5epy, 5etx

Cited: 19 times
EuropePMC logo PMID: 26682473

Abstract

Recent advances in direct-acting antivirals against Hepatitis C Virus (HCV) have led to the development of potent inhibitors, including MK-5172, that target the viral NS3/4A protease with relatively low susceptibility to resistance. MK-5172 has a P2-P4 macrocycle and a unique binding mode among current protease inhibitors where the P2 quinoxaline packs against the catalytic residues H57 and D81. However, the effect of macrocyclization on this binding mode is not clear, as is the relation between macrocyclization, thermodynamic stabilization, and susceptibility to the resistance mutation A156T. We have determined high-resolution crystal structures of linear and P1-P3 macrocyclic analogs of MK-5172 bound to WT and A156T protease and compared these structures, their molecular dynamics, and experimental binding thermodynamics to the parent compound. We find that the "unique" binding mode of MK-5172 is conserved even when the P2-P4 macrocycle is removed or replaced with a P1-P3 macrocycle. While beneficial to decreasing the entropic penalty associated with binding, the constraint exerted by the P2-P4 macrocycle prevents efficient rearrangement to accommodate the A156T mutation, a deficit alleviated in the linear and P1-P3 analogs. Design of macrocyclic inhibitors against NS3/4A needs to achieve the best balance between exerting optimal conformational constraint for enhancing potency, fitting within the substrate envelope and allowing adaptability to be robust against resistance mutations.

Articles - 5eqq mentioned but not cited (2)

  1. Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants. Rusere LN, Matthew AN, Lockbaum GJ, Jahangir M, Newton A, Petropoulos CJ, Huang W, Kurt Yilmaz N, Schiffer CA, Ali A. ACS Med Chem Lett 9 691-696 (2018)
  2. Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir. Timm J, Kosovrasti K, Henes M, Leidner F, Hou S, Ali A, Kurt Yilmaz N, Schiffer CA. ACS Chem Biol 15 342-352 (2020)


Reviews citing this publication (3)

  1. Improving Viral Protease Inhibitors to Counter Drug Resistance. Kurt Yilmaz N, Swanstrom R, Schiffer CA. Trends Microbiol 24 547-557 (2016)
  2. Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond. Matthew AN, Leidner F, Lockbaum GJ, Henes M, Zephyr J, Hou S, Rao DN, Timm J, Rusere LN, Ragland DA, Paulsen JL, Prachanronarong K, Soumana DI, Nalivaika EA, Kurt Yilmaz N, Ali A, Schiffer CA. Chem Rev 121 3238-3270 (2021)
  3. Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors. Özen A, Prachanronarong K, Matthew AN, Soumana DI, Schiffer CA. Crit Rev Biochem Mol Biol 54 11-26 (2019)

Articles citing this publication (14)

  1. Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach. Iftikhar H, Ali HN, Farooq S, Naveed H, Shahzad-Ul-Hussan S. Comput Biol Med 122 103848 (2020)
  2. Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease. Soumana DI, Kurt Yilmaz N, Ali A, Prachanronarong KL, Schiffer CA. J Am Chem Soc 138 11850-11859 (2016)
  3. Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants. Matthew AN, Zephyr J, Hill CJ, Jahangir M, Newton A, Petropoulos CJ, Huang W, Kurt-Yilmaz N, Schiffer CA, Ali A. J Med Chem 60 5699-5716 (2017)
  4. Validation and correction of Zn-CysxHisy complexes. Touw WG, van Beusekom B, Evers JM, Vriend G, Joosten RP. Acta Crystallogr D Struct Biol 72 1110-1118 (2016)
  5. Viral proteases: Structure, mechanism and inhibition. Zephyr J, Kurt Yilmaz N, Schiffer CA. Enzymes 50 301-333 (2021)
  6. Mechanistic and Structural Features of PROTAC Ternary Complexes. Casement R, Bond A, Craigon C, Ciulli A. Methods Mol Biol 2365 79-113 (2021)
  7. Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A Protease. Matthew AN, Leidner F, Newton A, Petropoulos CJ, Huang W, Ali A, KurtYilmaz N, Schiffer CA. Structure 26 1360-1372.e5 (2018)
  8. Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors. Matthew AN, Zephyr J, Nageswara Rao D, Henes M, Kamran W, Kosovrasti K, Hedger AK, Lockbaum GJ, Timm J, Ali A, Kurt Yilmaz N, Schiffer CA. mBio 11 e00172-20 (2020)
  9. Identification of potential inhibitors for HCV NS3 genotype 4a by combining protein-ligand interaction fingerprint, 3D pharmacophore, docking, and dynamic simulation. El-Hasab MAE, El-Bastawissy EE, El-Moselhy TF. J Biomol Struct Dyn 36 1713-1727 (2018)
  10. Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants. Nageswara Rao D, Zephyr J, Henes M, Chan ET, Matthew AN, Hedger AK, Conway HL, Saeed M, Newton A, Petropoulos CJ, Huang W, Kurt Yilmaz N, Schiffer CA, Ali A. J Med Chem 64 11972-11989 (2021)
  11. QSAR studies of the bioactivity of hepatitis C virus (HCV) NS3/4A protease inhibitors by multiple linear regression (MLR) and support vector machine (SVM). Qin Z, Wang M, Yan A. Bioorg Med Chem Lett 27 2931-2938 (2017)
  12. The NS4A Cofactor Dependent Enhancement of HCV NS3 Protease Activity Correlates with a 4D Geometrical Measure of the Catalytic Triad Region. Hamad HA, Thurston J, Teague T, Ackad E, Yousef MS. PLoS One 11 e0168002 (2016)
  13. Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance. Zephyr J, Nageswara Rao D, Vo SV, Henes M, Kosovrasti K, Matthew AN, Hedger AK, Timm J, Chan ET, Ali A, Kurt Yilmaz N, Schiffer CA. J Mol Biol 434 167503 (2022)
  14. Solid-Phase Synthesis of the Bicyclic Peptide OL-CTOP Containing Two Disulfide Bridges, and an Assessment of Its In Vivo μ-Opioid Receptor Antagonism after Nasal Administration. Rayala R, Tiller A, Majumder SA, Stacy HM, Eans SO, Nedovic A, McLaughlin JP, Cudic P. Molecules 28 1822 (2023)


Related citations provided by authors (1)

  1. Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance.. Ali A, Aydin C, Gildemeister R, Romano KP, Cao H, Ozen A, Soumana D, Newton A, Petropoulos CJ, Huang W, Schiffer CA ACS Chem Biol 8 1469-78 (2013)

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