Advertisement

Structural Information and Drug–Enzyme Interaction of the Non-Nucleoside Reverse Transcriptase Inhibitors Based on Computational Chemistry Approaches

  • Supa HannongbuaEmail author
Chapter
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 4)

Abstract

Non-nucleoside reverse transcriptase inhibitors, such as nevirapine, TIBO, HEPT, and efavirenz, are very specific to HIV-1 reverse transcriptase and have few side effects compared to NRTIs. However, mutation of the HIV-1 virus has caused drug resistance to develop and reduce the efficiency of these inhibitors for drug therapy. As the association of NNRTIs with the binding pocket of the enzyme is essential for the inhibition process, this interaction is of high interest. Potential energy surface is used for conformational analysis of these flexible NNRTIs. The interactions between the inhibitor molecules and the surrounding amino acids are the key to determining the binding affinity. Much work has been done by using the 3D-QSAR method, with detailed molecular structural analysis of HIV-1 inhibitors by theoretical calculations, including enzyme–inhibitor interactions. Accurate calculations of detailed interactions are demonstrated by multilayered integration or ONIOM method to give some insight into the particular interaction of the NNRTIs with the residues in the binding site. In addition, molecular dynamics simulations, Monte-Carlo simulations and protein-based inhibitor design methods have been applied extensively on these inhibitors. This review is an attempt to combine various QSAR and CAMD methods on NNRTIs into a common prediction model to support the design of new, more potent inhibitors, in particular, active against mutant enzyme prior to synthesis.

Drug-enzyme interaction Molecular simulations Non-nucleoside  reverse transcriptase inhibitor ONIOM Quantum chemical calculations 

Abbreviations

α-APA

(+/ −)-2,6-Dichloro-α-[(2-acetyl-5-methylphenyl)amino]benzamide

2D, 3D

Two dimensional, three dimensional

2D-QSAR

Two-dimensional quantitative structure–activity relationships

3D-QSAR

Three-dimensional quantitative structure–activity relationships

8-Cl TIBO

8-Chlorotetrahydroimidazo(4,5,1-jk)(1,4)-benzodiazepin-2(1H)-thione

9-Cl TIBO

9-Chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo(4,5,1-jk)(1,4)benzodiazepine-2-(1H)-thione

AIDS

Acquired immunodeficiency syndrome

AMBER

AMBER force field

ANN

Artificial neural network

Arg

Arginine

Asn

Asparagine

Asp

Aspartic acid

B3LYP

Beck's three-parameter exchange functional with Lee–Yang–Parr correlation

CAMD

Computer-aided molecular design

CC

Computational chemistry

cc-PVDZ

Correlation-consistent polarized valence double zeta

cc-PVTZ

Correlation-consistent polarized valence triple zeta

CoMFA

Comparative molecular field analysis

CoMSIA

Comparative molecular similarity indexes analysis

Cys

Cysteine

DFT

Density functional theory

DMA

N6-dimethylallyl

DNA

Deoxyribonucleic acid

dNTP

Deoxynucleotide triphosphate

EC50

Median effective concentration

FEP

Free energy perturbation

GIAO

Gauge-independent atomic orbital

Glu

Glutamic acid

Gly

Glycine

HEPT

1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine

HF

Hartree–Fock theory

His

Histidine

HIV-1

Human immunodeficiency virus type 1

HQSAR

Hologram quantitative structure–activity relationships

IC50

Median inhibitory concentration

IMOMO

Integrated molecular orbital molecular mechanics

Ile

Isoleucine

Leu

Leucine

Lys

Lysine

MC

Monte Carlo

MD

Molecular dynamics

MM3

Molecular mechanics, Allinger force field version 3

MP2

Second-order Møller–Plesset perturbation theory

MT-4

Human membrane type-4

NMR

Nuclear magnetic resonance

NNRTIs

Non-nucleoside reverse transcriptase inhibitors

NRTIs

Nucleoside reverse transcriptase inhibitors

ONIOM

Our own N-layered integrated molecular orbital and molecular mechanics method

p51

Peptide having molecular weight 51 kDA

p66

Peptide having molecular weight 66 kDA

PASs

Pyrrolyl aryl sulfones

PDBS

Pharmacophore-based database searching

PES

Potential energy surface

PETT

Phenylethylthiazolylthiourea

Phe

Phenylalanine

PM3

Modified neglect of diatomic overlap, parametric method number 3

Pro

Proline

QC

Quantum chemistry

QM/MM

Quantum mechanics and molecular mechanics

QM/QM

Quantum mechanics and quantum mechanics

QSAR

Quantitative structure–activity relationships

RCSB PDB

Research Collaboratory for Structural Bioinformatics (RCSB), the non-profit consortium that manages the Protein Data Bank (PDB)

RNA

Ribonucleic acid

RNaseH

Ribonuclease H

RT

Reverse transcriptase

SEAL

Steric and electrostatic alignment

Ser

Serine

SI

Selectivity index

SMD

Steered molecular dynamics

SMF

Substructural molecular fragments

SOM

Self-organizing map

TCs

Thiocarbamates

Thr

Threonine

TIBO

S-(+)-4,5,6,7-Tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]-benzodiazepin-2-(1H)-thione

Trp

Tryptophan

Tyr

Tyrosine

UFF

Universal force field

Val

Valine

WT

Wild type

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgments

The author thanks Prof. Gupta for his encouragement in writing this review and Prof. Wolschann for many useful suggestions. Financial support from the Thailand Research Fund (BRG4780007) and National Research Council of Thailand (1.AU 49/2547), Postgraduates on Education and Research on Petroleum and Petrochemical Technology and KURDI are gratefully acknowledged. Thanks are due to Patchareenart Saparpakorn for excellent assistance in preparation of the manuscript and to W.J. Holzschuh for reading the manuscript.

References

  1. 1.
    Jonckheere H, Annè J, De Clerq E (2000) Med Res Rev 20:129 CrossRefGoogle Scholar
  2. 2.
    De Clercq E (2001) J Clin Virol 22:73 CrossRefGoogle Scholar
  3. 3.
    De Clercq E (2002) Biochim Biophys Acta 1587:258 Google Scholar
  4. 4.
    De Clercq E (2004) Chem Biodiver 1:44 CrossRefGoogle Scholar
  5. 5.
    De Clercq E (1998) Antiviral Res 38:153 CrossRefGoogle Scholar
  6. 6.
    Lawtrakul L, Beyer A, Hannongbua S, Wolschann P (2004) Monatsh Chem 135:1033 Google Scholar
  7. 7.
    Beyer A, Lawtrakul L, Hannongbua S, Wolschann P (2004) Monatsh Chem 135:1047 Google Scholar
  8. 8.
    Ren J, Esnouf R, Garman E, Somers D, Ross C, Kirby I, Keeling J, Darby G, Jones Y, Stuart D, Stammers D (1995) Nat Struct Biol 2:293 CrossRefGoogle Scholar
  9. 9.
    Buckheit RW, Fliakas-Boltz V, Yeagy-Bargo S, Weislow O, Mayers DL, Boyer PL, Hughes SH, Pan BC, Chu SH, Bader JP (1995) Virology 210:186 CrossRefGoogle Scholar
  10. 10.
    Richman D, Shih CK, Lowy I, Rose J, Prodanovich P, Goff S, Griffin J (1991) Proc Natl Acad Sci USA 88:11241 CrossRefGoogle Scholar
  11. 11.
    Berman HM, Westbrook J, Feng Z, Gililand G, Bhat TN, Weissing H, Shindyalov IN, Bourne PE (2000) Nucleic Acids Res 28:235 CrossRefGoogle Scholar
  12. 12.
    Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Science 256:1783 CrossRefGoogle Scholar
  13. 13.
    Rodgers DW, Gamblin SJ, Harris BA, Ray S, Culp JS, Hellmig B, Woolf DJ, Debouck CD, Harrison SC (1995) Proc Natl Acad Sci USA 92:1222 CrossRefGoogle Scholar
  14. 14.
    Wang J, Smerdon SJ, Jager J, Kohlstaedt LA, Rice PA, Friedman JM, Steitz TA (1994) Proc Natl Acad Sci USA 91:7472 Google Scholar
  15. 15.
    Ren J, Nichols C, Bird L, Chamberlain P, Weaver K, Short S, Stuart DI, Stammer DK (2001) J Mol Biol 312:795 CrossRefGoogle Scholar
  16. 16.
    Lindberg J, Sigurdsson S, Löwgren S, Andersson HO, Sahlberg C, Noreen R, Fridborg K, Zhang H, Unge T (2002) Eur J Biochem 269:1670 CrossRefGoogle Scholar
  17. 17.
    Shafer RW, Kantor R, Gonzales MJ (2000) AIDS Rev 2:211 Google Scholar
  18. 18.
    Carloni P, Alber F (eds) (2003) Quantum medicinal chemistry. Wiley, Weinheim CrossRefGoogle Scholar
  19. 19.
    Höltje H-D, Sippl W, Rognan D, Folkers G (eds) (2003) Molecular modelling: basic principles and applications, 2nd edn. Wiley, Weinheim Google Scholar
  20. 20.
    Graves JD, Krebs EG (1999) Pharmacol Ther 82:111 CrossRefGoogle Scholar
  21. 21.
    Varnai P, Richards WG, Lyne PD (1999) Proteins 37:218 CrossRefGoogle Scholar
  22. 22.
    Ridder L, Rietjens IMCM, Vervoort J, Mulholland AJ (2002) J Am Chem Soc 124:9926 CrossRefGoogle Scholar
  23. 23.
    Laio A, Vandevondele J, Röthlisberger U (2002) J Chem Phys 116:6941 CrossRefGoogle Scholar
  24. 24.
    Laio A, Vandevondele J, Röthlisberger U (2002) J Phys Chem B 106:7300 CrossRefGoogle Scholar
  25. 25.
    Davies MS, Berners-Price SJ, Hambley TW (2000) Inorg Chem 39:5603 CrossRefGoogle Scholar
  26. 26.
    Legendre F, Bas V, Kozeika J (2000) Chem Eur J 6:2002 CrossRefGoogle Scholar
  27. 27.
    Davies MS, Berners-Price SJ, Hambley TW (1998) J Am Chem Soc 120:11380 CrossRefGoogle Scholar
  28. 28.
    Leach AR (1996) Molecular modelling: principles and applications. Longman, Essex Google Scholar
  29. 29.
    Kubinyi H (1993) QSAR:Hansch analysis and related approaches. In: Mannhold R, Krogsgarrd Larsen P, Timmerman H (eds) Methods and principles in medicinal chemistry, vol 1. Wiley, Weinheim Google Scholar
  30. 30.
    Kubinyi H (ed) (1993) 3D QSAR in drug design: theory, methods and applications. ESCOM, Leiden Google Scholar
  31. 31.
    Gupta SP, Garg RJ (1996) Enz Inh 11:23 CrossRefGoogle Scholar
  32. 32.
    Barreca ML, Carotti A, Rao A (1999) Bioorg Med Chem 7:2283 CrossRefGoogle Scholar
  33. 33.
    Silverman BD, Platt DE (1996) J Med Chem 39:2129 CrossRefGoogle Scholar
  34. 34.
    Luco JM, Ferritti FH (1997) J Chem Inf Comp Sci 37:392 CrossRefGoogle Scholar
  35. 35.
    Tronchet JMJ, Grigorov M, Dolatshahi N, Moriaud F, Weber JA (1997) Eur J Med Chem 32:279 CrossRefGoogle Scholar
  36. 36.
    Jalali-Heravi M, Parastar F (2000) J Chem Inf Comp Sci 40:147 CrossRefGoogle Scholar
  37. 37.
    Gussio R, Pattabiraman N, Zaharevitz DW, Kellogg GE, Toplo IA, Rice WG, Schaeffer CA, Erickson JW, Burt SK (1996) J Med Chem 39:1645 CrossRefGoogle Scholar
  38. 38.
    Hopfinger AJ, Duraiswami C (1997) J Am Chem Soc 119:10509 CrossRefGoogle Scholar
  39. 39.
    Hannongbua S, Lawtrakul L, Limtrakul J (1996) J Comput Aided Mol Des 10:145 CrossRefGoogle Scholar
  40. 40.
    Hannongbua S, Pungpo P, Limtrakul J, Wolschann P (1999) J Comput Aided Mol Des 13:563 CrossRefGoogle Scholar
  41. 41.
    Hall LH, Kier LB (1992) Rev Comput Chem 2:367 CrossRefGoogle Scholar
  42. 42.
    Randic M (1975) J Am Chem Soc 97:6609 CrossRefGoogle Scholar
  43. 43.
    Balaban AT (1982) Chem Phys Lett 89:399 CrossRefGoogle Scholar
  44. 44.
    Prasithichokekul S, Pungpo P, Hannongbua S, Ecker G, Wolschann P (2001) In: Proceedings of the 5th annual national symposium on computational science and engineering. Academic, Bangkok, p 351 Google Scholar
  45. 45.
    Hannongbua S, Nivasanond K, Lawtrakul L, Pungpo P, Wolschann P (2001) J Chem Inf Comput Sci 41:848 CrossRefGoogle Scholar
  46. 46.
    Pungpo P, Hannongbua S (2000) J Mol Graph Mod 18:581 CrossRefGoogle Scholar
  47. 47.
    Pungpo P, Hannongbua S, Wolschann P (2003) Curr Med Chem 10:1661 CrossRefGoogle Scholar
  48. 48.
    Medina-Franco JL, Rodriguez-Morales S, Juarez-Gordiano C, Hernandez-Campos A, Castillo R (2004) J Comp Aided Mol Des 18:345 CrossRefGoogle Scholar
  49. 49.
    Klabe G, Abraham U, Mietzner T (1994) J Med Chem 37:4130 CrossRefGoogle Scholar
  50. 50.
    Samee W, Ungwitayatorn J, Matayatsuk C, Pimthon J (2004) Science Asia 30:81 CrossRefGoogle Scholar
  51. 51.
    Zhou Z, Madura JD (2004) J Chem Inf Comput Sci 44:2167 CrossRefGoogle Scholar
  52. 52.
    Chen HF, Yao XJ, Li Q, Yuan SG, Panaye A, Doucet JP, Fan BT (2003) SAR QSAR Environ Res 14:455 CrossRefGoogle Scholar
  53. 53.
    Ishiki HM, Galembeck SE, do Amaral AT (2001) Rational approaches to drug design. In: Proceedings of the 13th European symposium on quantitative structure–activity relationships, Duesseldorf, Germany, 27 Aug–1 Sept, 2000. Prous Science, Barcelona, p 340 Google Scholar
  54. 54.
    Kireev DB, Chretien JR, Grierson DS, Monneret C (1997) J Med Chem 40:4257 CrossRefGoogle Scholar
  55. 55.
    Hopkins AL, Ren J, Esnouf RM, Willcox BE, Jones EY, Ross C, Miyasaka T, Walker RT, Tanaka H, Stammers DK, Stuart DI (1996) J Med Chem 39:1589 CrossRefGoogle Scholar
  56. 56.
    Parreira RLT, Abrahao O, Galembeck SE (2001) Tetrahedron 57:3243 CrossRefGoogle Scholar
  57. 57.
    Chimirri A, Grasso S, Monforte A-M, Monforte P, Rao A, Zappala M, Bruno G, Nicolo F, Scopelliti R (1997) Farmaco 52:673 Google Scholar
  58. 58.
    Lawtrakul L, Hannongbua S, Beyer A, Wolschann P (1999) Biol Chem 380:265 CrossRefGoogle Scholar
  59. 59.
    Lawtrakul L, Hannongbua S, Beyer A, Wolschann P (1999) Monatsh Chem 130:1347 Google Scholar
  60. 60.
    Hannongbua S, Prasithichokekul S, Pungpo P (2001) J Comput Aided Mol Des 15:997 CrossRefGoogle Scholar
  61. 61.
    Abrahao O, Nascimento PBD, Galembeck SE (2001) J Comput Chem 22:1817 CrossRefGoogle Scholar
  62. 62.
    Hannongbua S, Saen-oon S, Pungpo P, Wolschann P (2001) Monatsh Chem 132:1157 Google Scholar
  63. 63.
    Saen-oon S, Wolschann P, Hannongbua S (2003) J Chem Inf Comp Sci 43:1412 CrossRefGoogle Scholar
  64. 64.
    Das K, Lewi PJ, Hughes SH, Arnold E (2005) Prog Biophys Mol Biol 88:209 CrossRefGoogle Scholar
  65. 65.
    Vreven T, Morokuma K, Farkas O, Schlegel HB, Frisch MJ (2003) J Comput Chem 24:760 CrossRefGoogle Scholar
  66. 66.
    Zhang Y, Kua J, McCammon JA (2002) J Am Chem Soc 124:10572 CrossRefGoogle Scholar
  67. 67.
    Decker SA, Cundari TR (2001) J Organomet Chem 635:132 CrossRefGoogle Scholar
  68. 68.
    Guo QC, Lipscomb WN, Karplus M (2001) Proc Natl Acad Sci USA 98:9032 CrossRefGoogle Scholar
  69. 69.
    Maseras F, Morokuma K (1995) J Comput Chem 16:1170 CrossRefGoogle Scholar
  70. 70.
    Kuno M, Hannongbua S, Morokuma K (2003) Chem Phys Letts 380:456 CrossRefGoogle Scholar
  71. 71.
    Saen-oon S, Kuno M, Hannongbua S (2005) Proteins 61:859 CrossRefGoogle Scholar
  72. 72.
    Nunrium P, Kuno M, Saen-oon S, Hannongbua S (2005) Chem Phys Letts 405:198 CrossRefGoogle Scholar
  73. 73.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA, Vreven JrT, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Daniels AD, Farkas O, Rabuck AD, Raghavachari K, Ortiz JV (2003) GAUSSIAN03. Gaussian, Pittsburgh, PA Google Scholar
  74. 74.
    Dapprich ST, Komaromi I, Byun KS, Morokuma K, Frisch MJ (1999) J Mol Struct THEOCHEM 462:1 CrossRefGoogle Scholar
  75. 75.
    Kerdcharoen T, Morokuma K (2002) Chem Phys Letts 355:257 CrossRefGoogle Scholar
  76. 76.
    Frenkel D, Smit B (eds) (1996) Understanding molecular simulation: from algorithms to applications. Academic, Chestnut Hill Google Scholar
  77. 77.
    Zhou Z, Madrid M, Evansak JD, Madura JD (2005) J Am Chem Soc 127:17253 CrossRefGoogle Scholar
  78. 78.
    Shen L, Shen J, Luo X, Cheng F, Xu Y, Chen K, Arnold E, Ding J, Jiang H (2003) Biophys J 84:3547 CrossRefGoogle Scholar
  79. 79.
    Rodriguez-Barrios F, Balzarini J, Gago F (2005) J Am Chem Soc 127:7570 CrossRefGoogle Scholar
  80. 80.
    Weinzinger P, Hannongbua S, Wolschann P (2005) J Enz Inh Med Chem 20:129 CrossRefGoogle Scholar
  81. 81.
    Rizzo RC, Udier-Blagovic M, Wang DE-P, Watkins EK, Kroeger S, Marilyn B, Smith RH, Tirado-Rives J, Jorgensen WL, Western MC (2002) J Med Chem 45:2970 CrossRefGoogle Scholar
  82. 82.
    Wang DP, Rizzo RC, Tirado-Rives J, Jorgensen WL (2001) Bioorg Med Chem Lett 11:2799 CrossRefGoogle Scholar
  83. 83.
    Smith MBK, Lamb ML, Tirado-Rives J, Jorgensen WL, Michejda CJ, Ruby SK, Smith RH Jr (2000) Protein Eng 13:413 CrossRefGoogle Scholar
  84. 84.
    Weber HP (1994) J Comput Aided Mol Des 8:1 CrossRefGoogle Scholar
  85. 85.
    Colman PM (1994) Curr Opin Struct Biol 4:868 CrossRefGoogle Scholar
  86. 86.
    Kuntz ID (1992) Science 257:1078 CrossRefGoogle Scholar
  87. 87.
    Gubernator K, Böhm H (1997) Structure-based ligand design. In: Mannhold R, Krogsgarrd Larsen P, Timmerman H (eds) Methods and principles in medicinal chemistry, vol 6. Wiley, Weinheim Google Scholar
  88. 88.
    Ranise A, Spallarossa A, Cesarini S, Bondavalli F, Schenone S, Bruno O, Menozzi G, Fossa P, Mosti L, La Colla M, Sanna G, Murreddu M, Collu G, Busonera B, Marongiu ME, Pani A, La Colla P, Loddo R (2005) J Med Chem 48:3858 CrossRefGoogle Scholar
  89. 89.
    Silvestri R, Artico M, De Martino G, Novellino E, Greco G, Lavecchia A, Massa S, Loi AG, Doratiotto S, La Colla P (2000) Bioorg Med Chem 8:2305 CrossRefGoogle Scholar
  90. 90.
    Artico M, Silvestri R, Pagnozzi E, Bruno B, Novellino E, Greco G, Massa S, Ettorre A, Loi AG, Scintu F, La Colla P (2000) J Med Chem 43:1886 CrossRefGoogle Scholar
  91. 91.
    Good AC, Krystek SR, Mason JS (2000) Drug Discov Today 5:S61 CrossRefGoogle Scholar
  92. 92.
    Shoichet BK, McGovern SL, Wei B, Irwin JJ (2002) Curr Opin Chem Biol 6:439 CrossRefGoogle Scholar
  93. 93.
    Abagyan R, Totrov M (2001) Curr Opin Chem Biol 5:375 CrossRefGoogle Scholar
  94. 94.
    Hemmateenejad B, Tabaei S, Mohammad H, Namvaran F (2005) J Mol Struct THEOCHEM 732:39 CrossRefGoogle Scholar
  95. 95.
    Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (2001) Autodock reference manual, version 3.0.5. Scripps Research Institute, La Jolla, CA Google Scholar
  96. 96.
    Varnek A, Solov'ev VP (2005) Comb Chem High Throughput Screen 8:403 CrossRefGoogle Scholar
  97. 97.
    Shen J, Zu X, Feng C, Liu H, Luo X, Shen J, Chem K, Zhao W, Shen X, Jiang H (2003) Curr Med Chem 10:1241 Google Scholar
  98. 98.
    Sangma C, Chuakheaw D, Jongkon N, Saenbandit K, Nunrium P, Uthayopas P, Hannongbua S (2005) Comb Chem High Throughput Screen 8:417 CrossRefGoogle Scholar
  99. 99.
    Maiorov V, Sheridan RP (2005) J Chem Inf Comput Sci 45:1017 Google Scholar
  100. 100.
    Totrov M, Abagyan R (1997) Proteins 1(Suppl):215 Google Scholar
  101. 101.
    Xue L, Godden JW, Stahura FL, Bajorath J (2004) J Chem Inf Comput Sci 44:1275 CrossRefGoogle Scholar
  102. 102.
    Li H, Li C, Gui C, Luo X, Chen K, Shen J, Wang X, Jiang H (2004) Bioorg Med Chem Lett 14:4671 CrossRefGoogle Scholar

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of ScienceKasetsart UniversityBangkokThailand

Personalised recommendations