Theoretical investigation on nevirapine and HIV-1 reverse transcriptase binding site interaction, based on ONIOM method

The ONIOM method was applied to the interaction of nevirapine with the HIV-1 reverse transcriptase binding site. The isolated complex of pyridine (part of nevirapine) and methyl phenol (part of Tyr181) was found at the MP2/6-31+G(d) level to have stacking interaction with 8.8 kcal/mol binding energy. Optimization of nevirapine and Tyr181 geometry in the pocket of 16 amino acid residues at the ONIOM3(MP2/6-31G(d):HF/3-21G:PM3) level gave the complex structure with weak hydrogen bonding but without stacking interaction. The binding energy of 8.9 kcal/mol comes almost entirely from the interaction of nevirapine with amino acid residues other than Tyr181.

[1]  Keiji Morokuma,et al.  The IMOMO method: Integration of different levels of molecular orbital approximations for geometry optimization of large systems: Test for n‐butane conformation and SN2 reaction: RCl+Cl− , 1996 .

[2]  S. Galembeck,et al.  Conformational preferences of non-nucleoside HIV-1 reverse transcriptase inhibitors , 2001 .

[3]  Peter Pulay,et al.  CAN (SEMI) LOCAL DENSITY FUNCTIONAL THEORY ACCOUNT FOR THE LONDON DISPERSION FORCES , 1994 .

[4]  P. Kollman,et al.  Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA. , 2001, Journal of the American Chemical Society.

[5]  K. Morokuma,et al.  A NEW ONIOM IMPLEMENTATION IN GAUSSIAN98. PART I. THE CALCULATION OF ENERGIES, GRADIENTS, VIBRATIONAL FREQUENCIES AND ELECTRIC FIELD DERIVATIVES , 1999 .

[6]  A. Skalka,et al.  The retroviral enzymes. , 1994, Annual review of biochemistry.

[7]  H. Mitsuya,et al.  Molecular targets for AIDS therapy. , 1990, Science.

[8]  E. Clercq.  HIV resistance to reverse transcriptase inhibitors , 1994 .

[9]  A. Becke.  Density-functional thermochemistry. III. The role of exact exchange , 1993 .

[10]  K. Morokuma,et al.  ONIOM: A Multilayered Integrated MO + MM Method for Geometry Optimizations and Single Point Energy Predictions. A Test for Diels−Alder Reactions and Pt(P(t-Bu)3)2 + H2 Oxidative Addition , 1996 .

[11]  A. Becke,et al.  Density-functional exchange-energy approximation with correct asymptotic behavior. , 1988, Physical review. A, General physics.

[12]  E. De Clercq,et al.  The HIV‐1 Reverse Transcription (RT) Process as Target for RT Inhibitors , 2000, Medicinal research reviews.

[13]  P. Wolschann,et al.  Molecular Calculations on the Conformation of the HIV-1 Reverse Transcriptase Inhibitor (+)-(S)-4,5,6,7-Tetrahydro-8-chloro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4] benzodiazepine-2(1H)-thione (8-Chloro-TIBO) , 2001 .

[14]  Hans Peter Lüthi,et al.  Interaction energies of van der Waals and hydrogen bonded systems calculated using density functional theory: Assessing the PW91 model , 2001 .

[15]  Supa Hannongbua,et al.  Conformational analysis of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, based on quantum mechanical calculations , 2001, J. Comput. Aided Mol. Des..

[16]  Feliu Maseras,et al.  IMOMM: A new integrated ab initio + molecular mechanics geometry optimization scheme of equilibrium structures and transition states , 1995, J. Comput. Chem..

[17]  J Tirado-Rives,et al.  Estimation of binding affinities for HEPT and nevirapine analogues with HIV-1 reverse transcriptase via Monte Carlo simulations. , 2001, Journal of medicinal chemistry.