Unbinding Dynamics of Non-Nucleoside Inhibitors from HIV-1 Reverse Transcriptase

Overview

Journal J Phys Chem B

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Dec 21

PMID 30571126

Citations 8

Authors

Leela S Dodda

Julian Tirado-Rives

William L Jorgensen

Affiliations

Soon will be listed here.

Abstract

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs), which bind to an allosteric site 10-15 Å from the polymerase active site, play a central role in anti-HIV chemotherapy. Though NNRTIs have been known for 30 years, the pathways by which they bind and unbind from HIV-RT have not been characterized. In crystal structures for complexes, three channels are found to extend from the NNRTI binding site to the exterior of the protein, while added mystery comes from the fact that the binding site is collapsed in the unliganded protein. To address this issue, metadynamics simulations have been performed to elucidate the unbinding of four NNRTIs from HIV-RT. A general and transferable collective variable defined by the distance between the center-of-mass (COM) of the binding pocket and COM of the ligand is used to follow the dynamics while minimizing the bias. The metadynamics also allows computation of the barriers to unbinding, which are compared with the observed potencies of the compounds in an antiviral assay.

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References

Madrid M, Lukin J, Madura J, Ding J, Arnold E . Molecular dynamics of HIV-1 reverse transcriptase indicates increased flexibility upon DNA binding. Proteins. 2001; 45(3):176-82. DOI: 10.1002/prot.1137. View

Laio A, Parrinello M . Escaping free-energy minima. Proc Natl Acad Sci U S A. 2002; 99(20):12562-6. PMC: 130499. DOI: 10.1073/pnas.202427399. View

Shen L, Shen J, Luo X, Cheng F, Xu Y, Chen K . Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT. Biophys J. 2003; 84(6):3547-63. PMC: 1302942. DOI: 10.1016/S0006-3495(03)75088-7. View

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

Jorgensen W, Tirado-Rives J . Potential energy functions for atomic-level simulations of water and organic and biomolecular systems. Proc Natl Acad Sci U S A. 2005; 102(19):6665-70. PMC: 1100738. DOI: 10.1073/pnas.0408037102. View

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View

Ruiz-Caro J, Basavapathruni A, Kim J, Bailey C, Wang L, Anderson K . Optimization of diarylamines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett. 2005; 16(3):668-71. DOI: 10.1016/j.bmcl.2005.10.037. View

Zhou Z, Madrid M, Evanseck J, Madura J . Effect of a bound non-nucleoside RT inhibitor on the dynamics of wild-type and mutant HIV-1 reverse transcriptase. J Am Chem Soc. 2005; 127(49):17253-60. DOI: 10.1021/ja053973d. View

Thakur V, Kim J, Hamilton A, Bailey C, Domaoal R, Wang L . Optimization of pyrimidinyl- and triazinyl-amines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett. 2006; 16(21):5664-7. DOI: 10.1016/j.bmcl.2006.08.037. View

10.

Ivetac A, McCammon J . Elucidating the inhibition mechanism of HIV-1 non-nucleoside reverse transcriptase inhibitors through multicopy molecular dynamics simulations. J Mol Biol. 2009; 388(3):644-58. PMC: 2744402. DOI: 10.1016/j.jmb.2009.03.037. View

11.

Leung C, Zeevaart J, Domaoal R, Bollini M, Thakur V, Spasov K . Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives. Bioorg Med Chem Lett. 2010; 20(8):2485-8. PMC: 2880392. DOI: 10.1016/j.bmcl.2010.03.006. View

12.

Ekkati A, Bollini M, Domaoal R, Spasov K, Anderson K, Jorgensen W . Discovery of dimeric inhibitors by extension into the entrance channel of HIV-1 reverse transcriptase. Bioorg Med Chem Lett. 2012; 22(4):1565-8. PMC: 3278212. DOI: 10.1016/j.bmcl.2011.12.132. View

13.

Reynolds C, de Koning C, Pelly S, van Otterlo W, Bode M . In search of a treatment for HIV--current therapies and the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Chem Soc Rev. 2012; 41(13):4657-70. DOI: 10.1039/c2cs35058k. View

14.

Bailey C, Sullivan T, Iyidogan P, Tirado-Rives J, Chung R, Ruiz-Caro J . Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy. J Med Chem. 2013; 56(10):3959-68. PMC: 3733247. DOI: 10.1021/jm400160s. View

15.

De Clercq E . The nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors in the treatment of HIV infections (AIDS). Adv Pharmacol. 2013; 67:317-58. DOI: 10.1016/B978-0-12-405880-4.00009-3. View

16.

Bollini M, Frey K, Cisneros J, Spasov K, Das K, Bauman J . Extension into the entrance channel of HIV-1 reverse transcriptase--crystallography and enhanced solubility. Bioorg Med Chem Lett. 2013; 23(18):5209-12. PMC: 3761378. DOI: 10.1016/j.bmcl.2013.06.093. View

17.

Vijayan R, Arnold E, Das K . Molecular dynamics study of HIV-1 RT-DNA-nevirapine complexes explains NNRTI inhibition and resistance by connection mutations. Proteins. 2013; 82(5):815-29. PMC: 4502926. DOI: 10.1002/prot.24460. View

18.

Bellucci L, Angeli L, Tafi A, Radi M, Botta M . Unconventional plasticity of HIV-1 reverse transcriptase: how inhibitors could open a connection "gate" between allosteric and catalytic sites. J Chem Inf Model. 2013; 53(12):3117-22. DOI: 10.1021/ci400414s. View

19.

Iyidogan P, Anderson K . Current perspectives on HIV-1 antiretroviral drug resistance. Viruses. 2014; 6(10):4095-139. PMC: 4213579. DOI: 10.3390/v6104095. View

20.

Lee W, Frey K, Gallardo-Macias R, Spasov K, Bollini M, Anderson K . Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers. ACS Med Chem Lett. 2014; 5(11):1259-62. PMC: 4233359. DOI: 10.1021/ml5003713. View