Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance

Journal of Medicinal Chemistry

Volumn 55, Issue 14, 2012, Pages 6328-6341

  Parai, Maloy Kumar ^a   Huggins, David J ^b   Cao, Hong ^c   Nalam, Madhavi N L ^c   Ali, Akbar ^c   Schiffer, Celia A ^c   Tidor, Bruce ^b   Rana, Tariq M ^a,c  

^a BURNHAM INSTITUTE   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^c UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(5 OXOPYRROLIDIN 2 YL)METHYL [3 HYDROXY 4 [N (2 METHYLBUTYL)BENZO[D]THIAZOLE 6 SULFONAMIDO] 1 PHENYLBUTAN 2 YL]CARBAMATE; 2 (2 OXOIMIDAZOLIDIN 1 YL)ETHYL 3 HYDROXY 4 [4 METHOXY N (2 METHYLBUTYL)PHENYLSULFONAMIDO] 1 PHENYLBUTAN 2 YLCARBAMATE; 2 (2,2 DICHLOROACETAMIDO)ETHYL 3 HYDROXY 4 [4 METHOXY N (2 METHYLBUTYL)PHENYLSULFONAMIDO] 1 PHENYLBUTAN 2 YLCARBAMATE; HUMAN IMMUNODEFICIENCY VIRUS PROTEINASE INHIBITOR; METHYL 3 [[[3 HYDROXY 4 [4 METHOXY N (2 METHYLBUTYL)PHENYLSULFONAMIDO] 1 PHENYLBUTAN 2 YL]CARBAMOYL]OXY] 2 METHYLPROPANOATE; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING AFFINITY; CLADISTICS; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HYDROGEN BOND; MULTIDRUG RESISTANCE; NONHUMAN; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

CHEMISTRY TECHNIQUES, SYNTHETIC; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; DRUG RESISTANCE, MULTIPLE; DRUG RESISTANCE, VIRAL; HIV PROTEASE; HIV PROTEASE INHIBITORS; HIV-1; MODELS, MOLECULAR; PROTEIN CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84864235498     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300238h     Document Type: Article

References (50)

1. Bartlett, J. A.; DeMasi, R.; Quinn, J.; Moxham, C.; Rousseau, F. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults AIDS 2001, 15, 1369-1377
2. Gulick, R. M.; Mellors, J. W.; Havlir, D.; Eron, J. J.; Meibohm, A.; Condra, J. H.; Valentine, F. T.; McMahon, D.; Gonzalez, C.; Jonas, L.; Emini, E. A.; Chodakewitz, J. A.; Isaacs, R.; Richman, D. D. 3-Year suppression of HIV viremia with indinavir, zidovudine, and lamivudine Ann. Intern. Med. 2000, 133, 35-39
3. Palella, F. J.; Delaney, K. M.; Moorman, A. C.; Loveless, M. O.; Fuhrer, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. The, H. I. V. O. S. I. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection N. Engl. J. Med. 1998, 338, 853-860
4. Hogg, R. S.; Heath, K. V.; Yip, B.; Craib, K. J. P.; O'Shaughnessy, M. V.; Schechter, M. T.; Montaner, J. S. G. Improved survival among HIV-infected individuals following initiation of antiretroviral therapy JAMA, J. Am. Med. Assoc. 1998, 279, 450-454
5. Waters, L.; Nelson, M. Why do patients fail HIV therapy? Int. J. Clin. Pract. 2007, 61, 983-990
6. Condra, J. H.; Schleif, W. A.; Blahy, O. M.; Gabryelski, L. J.; Graham, D. J.; Quintero, J. C.; Rhodes, A.; Robbins, H. L.; Roth, E.; Shivaprakash, M.; Titus, D.; Yang, T.; Tepplert, H.; Squires, K. E.; Deutsch, P. J.; Emini, E. A. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors Nature 1995, 374, 569-571
7. Clavel, F.; Hance, A. J. HIV drug resistance N. Engl. J. Med. 2004, 350, 1023-1035
8. Prabu-Jeyabalan, M.; Nalivaika, E.; Schiffer, C. A. Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes Structure 2002, 10, 369-381
9. Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. A. Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme J. Am. Chem. Soc. 1995, 117, 1181-1182
10. Koh, Y.; Nakata, H.; Maeda, K.; Ogata, H.; Bilcer, G.; Devasamudram, T.; Kincaid, J. F.; Boross, P.; Wang, Y.-F.; Tie, Y.; Volarath, P.; Gaddis, L.; Harrison, R. W.; Weber, I. T.; Ghosh, A. K.; Mitsuya, H. Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro Antimicrob. Agents Chemother. 2003, 47, 3123-3129
11. Surleraux, D. L. N. G.; Tahri, A.; Verschueren, W. G.; Pille, G. M. E.; de Kock, H. A.; Jonckers, T. H.; Peeters, A.; De Meyer, S.; Azijn, H.; Pauwels, R.; de Bethune, M.-P.; King, N. M.; Prabu-Jeyabalan, M.; Schiffer, C. A.; Wigerinck, P. B. T. P. Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor J. Med. Chem. 2005, 48, 1813-1822
12. De Meyer, S.; Azijn, H.; Surleraux, D.; Jochmans, D.; Tahri, A.; Pauwels, R.; Wigerinck, P.; de Bethune, M. P. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates Antimicrob. Agents Chemother. 2005, 49, 2314-2321
13. King, N. M.; Prabu-Jeyabalan, M.; Nalivaika, E. A.; Wigerinck, P. B. T. P.; de Bethune, M. P.; Schiffer, C. A. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor J. Virol. 2004, 78, 12012-12021
14. Kovalevsky, A. Y.; Tie, Y.; Liu, F.; Boross, P. I.; Wang, Y.-F.; Leshchenko, S.; Ghosh, A. K.; Harrison, R. W.; Weber, I. T. Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M J. Med. Chem. 2006, 49, 1379-1387
15. Surleraux, D. L. N. G.; de Kock, H. A.; Verschueren, W. G.; Pille, G. M. E.; Maes, L. R.; Peeters, A.; Vendeville, S.; De Meyer, S.; Azijn, H.; Pauwels, R.; de Bethune, M. P.; King, N. M.; Prabu-Jeyabalan, M.; Schiffer, C. A.; Wigerinck, P. B. T. P. Design of HIV-1 protease inhibitors active on multidrug-resistant virus J. Med. Chem. 2005, 48, 1965-1973
16. Miller, J. F.; Andrews, C. W.; Brieger, M.; Furfine, E. S.; Hale, M. R.; Hanlon, M. H.; Hazen, R. J.; Kaldor, I.; McLean, E. W.; Reynolds, D.; Sammond, D. M.; Spaltenstein, A.; Tung, R.; Turner, E. M.; Xu, R. X.; Sherrill, R. G. Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: the discovery of GW0385 Bioorg. Med. Chem. Lett. 2006, 16, 1788-1794
17. He, G.-X.; Yang, Z.-Y.; Williams, M.; Callebaut, C.; Cihlar, T.; Murray, B. P.; Yang, C.; Mitchell, M. L.; Liu, H.; Wang, J.; Arimilli, M.; Eisenberg, E.; Stray, K. M.; Tsai, L. K.; Hatada, M.; Chen, X.; Chen, J. M.; Wang, Y.; Lee, M. S.; Strickley, R. G.; Iwata, Q.; Zheng, X.; Kim, C. U.; Swaminathan, S.; Desai, M. C.; Lee, W. A.; Xu, L. Discovery of GS-8374, a potent human immunodeficiency virus type 1 protease inhibitor with a superior resistance profile MedChemComm 2011, 2, 1093-1098
18. Ghosh, A. K.; Sridhar, P. R.; Leshchenko, S.; Hussain, A. K.; Li, J.; Kovalevsky, A. Y.; Walters, D. E.; Wedekind, J. E.; Grum-Tokars, V.; Das, D.; Koh, Y.; Maeda, K.; Gatanaga, H.; Weber, I. T.; Mitsuya, H. Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance J. Med. Chem. 2006, 49, 5252-5261
19. Ghosh, A. K.; Gemma, S.; Baldridge, A.; Wang, Y.-F.; Kovalevsky, A. Yu.; Koh, Y.; Weber, I. T.; Mitsuya, H. Flexible cyclic ethers/polyethers as novel P2-ligands for HIV-1 protease inhibitors: design, synthesis, biological evaluation, and protein-ligand X-ray studies J. Med. Chem. 2008, 51, 6021-6033
20. Ghosh, A. K.; Chapsal, B. D.; Baldridge, A.; Steffey, M. P.; Walters, D. E.; Koh, Y.; Amano, M.; Mitsuya, H. Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P2 ligands: structure-activity studies and biological evaluation J. Med. Chem. 2011, 54, 622-634
21. Ali, A.; Reddy, G. S. K. K.; Cao, H.; Anjum, S. G.; Nalam, M. N. L.; Schiffer, C. A.; Rana, T. M. Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N -aryl-oxazolidinone-5-carboxamides as novel P2 ligands J. Med. Chem. 2006, 49, 7342-7356
22. Ali, A.; Reddy, G. S. K. K.; Nalam, M. N. L.; Anjum, S. G.; Cao, H.; Schiffer, C. A.; Rana, T. M. Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones J. Med. Chem. 2010, 53, 7699-7708
23. Altman, M. D.; Ali, A.; Reddy, G. S. K. K.; Nalam, M. N. L.; Anjum, S. G.; Cao, H.; Chellappan, S.; Kairys, V.; Fernandes, M. X.; Gilson, M. K.; Schiffer, C. A.; Rana, T. M.; Tidor, B. HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants J. Am. Chem. Soc. 2008, 130, 6099-6113
24. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMM: a program for macromolecular energy, minimization, and dynamics calculations J. Comput. Chem. 1983, 4, 187-217
25. Momany, F. A.; Rone, R. Validation of the general purpose QUANTA 3.2/CHARMm force field J. Comput. Chem. 1992, 13, 888-900
26. Sitkoff, D.; Sharp, K. A.; Honig, B. Accurate calculation of hydration free energies using macroscopic solvent models J. Phys. Chem. 1994, 98, 1978-1988
27. Gilson, M. K.; Honig, B. Calculation of the total electrostatic energy of a macromolecular system: solvation energies, binding energies, and conformational analysis Proteins 1988, 4, 7-18
28. Nicholls, A.; Honig, B. A rapid finite difference algorithm, utilizing successive over-relaxation to solve the Poisson-Boltzmann equation J. Comput. Chem. 1991, 12, 435-445
29. Kangas, E.; Tidor, B. Optimizing electrostatic affinity in ligand-receptor binding: theory, computation, and ligand properties J. Chem. Phys. 1998, 109, 7522-7545
30. Gilson, M. K.; Sharp, K. A.; Honig, B. H. Calculating the electrostatic potential of molecules in solution: method and error assessment J. Comput. Chem. 1988, 9, 327-335
31. Irwin, J. J.; Shoichet, B. K. ZINC: a free database of commercially available compounds for virtual screening J. Chem. Inf. Model. 2005, 45, 177-182
32. Desmet, J.; Maeyer, M. D.; Hazes, B.; Lasters, I. The dead-end elimination theorem and its use in protein side-chain positioning Nature 1992, 356, 539-542
33. Leach, A. R.; Lemon, A. P. Exploring the conformational space of protein side chains using dead-end elimination and the A* algorithm Proteins 1998, 33, 227-239
34. Matayoshi, E. D.; Wang, G. T.; Krafft, G. A.; Erickson, J. Novel fluorogenic substrates for assaying retroviral proteases by resonance energy transfer Science 1990, 247, 954-958
35. Wu, T. D.; Schiffer, C. A.; Gonzales, M. J.; Taylor, J.; Kantor, R.; Chou, S.; Israelski, D.; Zolopa, A. R.; Fessel, W. J.; Shafer, R. W. Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments J. Virol. 2003, 77, 4836-4847
36. Nalam, M. N. L.; Ali, A.; Altman, M. D.; Reddy, G. S. K. K.; Chellappan, S.; Kairys, V.; Ozen, A.; Cao, H.; Gilson, M. K.; Tidor, B.; Rana, T. M.; Schiffer, C. A. Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance J. Virol. 2010, 84, 5368-5378
37. Freire, E. Do enthalpy and entropy distinguish first in class from best in class? Drug Discovery Today 2008, 13, 869-874
38. Bissantz, C.; Kuhn, B.; Stahl, M. A medicinal chemist's guide to molecular interactions J. Med. Chem. 2010, 53, 5061-5084
39. King, N. M.; Melnick, L.; Prabu-Jeyabalan, M.; Nalivaika, E. A.; Yang, S. S.; Gao, Y.; Nie, X.; Zepp, C.; Heefner, D. L.; Schiffer, C. A. Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease Protein Sci. 2002, 11, 418-429
40. Greco, W. R.; Hakala, M. T. Evaluation of methods for estimating the dissociation constant of tight binding enzyme inhibitors J. Biol. Chem. 1979, 254, 12104-12109
41. Petropoulos, C. J.; Parkin, N. T.; Limoli, K. L.; Lie, Y. S.; Wrin, T.; Huang, W.; Tian, H.; Smith, D.; Winslow, G. A.; Capon, D. J.; Whitcomb, J. M. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1 Antimicrob. Agents Chemother. 2000, 44, 920-928
42. Otwinowski, Z.; Minor, W.; Carter, C. W., Jr. Processing of X-ray diffraction data collected in oscillation mode Methods Enzymol. 1997, 276, 307-326
43. Collaborative computational project, number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. 1994, D50, 760-763.
44. Navaza, J. AMoRe: an automated package for molecular replacement Acta Crystallogr. 1994, A50, 157-163
45. Prabu-Jeyabalan, M.; Nalivaika, E.; Schiffer, C. A. How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease J. Mol. Biol. 2000, 301, 1207-1220
46. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics Acta Crystallogr. 2004, D60, 2126-2132
47. Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method Acta Crystallogr. 1997, D53, 240-255
48. Schomaker, V.; Trueblood, K. N. On the rigid-body motion of molecules in crystals Acta Crystallogr. 1968, B24, 63-76
49. Kuriyan, J.; Weis, W. I. Rigid protein motion as a model for crystallographic temperature factors Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 2773-2777
50. Tickle, I. J.; Moss, D. S. Modeling Rigid-Body Thermal Motion in Macromolecular Crystal Structure Refinement. In IUCr99 Computing School; IUCr: London, 1999.