Computational studies of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTI)

Author(s)

Odonírio Abrahão Júnior

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
• Defense date: 2001-07-16

Examining board members

Sergio Emanuel Galembeck; Antonia Tavares do Amaral; Rogério Custódio; Yuji Takahata; Richard John Ward

• Advisor: Sergio Emanuel Galembeck

Abstract

The inhibition of the reverse transcriptase of the HIV-1 (RT) is one of the approaches proposed to combat the Acquired Immuno-Deficiency Syndrome (AIDS). The protease and integrase enzymes are two other research goals against the virus. The RT inhibitors act causing the termination of the DNA grow during reverse transcription. These inhibitors can be classified in two groups based on the fact that their interaction occurs or not at the active site of the substract. Classified within the first group are drugs such as 2\', 3\'-dideoxynucleoside (ddN) derivatives, three of which are now licensed for clinical use: azidothymidine (AZT), dideoxycytidine (ddC), didehydrodideoxythymidine (d4T) and 3\'-thiadideoxycytidine (3TC) and are up-to-now the first option in the HIV-1 combat. The second group pertains to the non-nucleosides reverse transcriptase inhibitors of HIV-1 (NNRTI). These compound are non-competitive inhibitors structurally diverse, not acting at the active site but in a hydrophobic pocket proximal to the catalytic site, and are not effective against the HIV-2 virus. This thesis presents three types of computational studies of NNRTI. The first work presents the parameterization of compounds belonging the class of Tetrahydro-imidazo[4,5,1-jk] [1,4]-benzodiazepin-2-one (TIBO), in the Cornell et al. force field (J. Am. Chem Soc. 117 (1995) 5179) through ab initio and semi-empirical methods. The new parameters were used in the conformational analysis for TIBO R82913 and TIBO R79882. Various conformational search protocols were tested and the pseudo-systematic method SUMM led to the best results. A better understanding of the distribution of conformers was obtained through clustering techniques in the data reduction stages. lt was possible to reproduce various experimental data such as the crystallographic structures of the isolated or reverse transcriptase-complexed (RT) molecules. The proton-proton coupling constants (PHH) obtained for TIBO through NMR were also reproduced. Cremer and Pople puckering parameters enabled a precise description of both the conformation of the seven-membered rings and the relative position of the substituents on them. These parameters also demonstrated the efficiency and precision of the two-stage clustering method. ln the third chapter of this thesis a comparative molecular field analysis (CoMFA) of six different classes of NNTI was done. Initially a selection between forty-nine compounds was done based on the homogeneous biological activity index, available in the literature. Next data treatment was executed, following the CoMFA methodology. The existing structure/ activity correlation for the six NNRTI classes showed an excellent agreement with the molecular field data obtained in this research. Therefor, the CoMFA methodology showed to be appropriate for the investigation of new NNRTI substitutes, since it was capable of identifying regions of molecular similarities of the investigated molecules, based on the electrostatic and steric fields of these molecules. So, the contribution furnishing by a certain NNRTI class can be used to postulate molecular modification of another class of compounds. Finally, the results of an investigation using the density functional theory, DFT, of fifteen NNRTI in their bioactivity conformation, are present. Not only the results of the calculation were compared directly but also using graphical visualization methods, permitting the identification of molecular similarities. MEP contour maps were design on the two planes of the butterfly like shape conformation of NNRTI, revealing a pattern of similarity. Besides, the HOMO and LUMO frontier orbitals were analysed revealing great similarity. An amide group, present in one of the planes of each of the NNRTI investigated is also a farmacophoric pattern of these compounds. It is interesting to emphasising that a NBO analysis indicate a interaction of the type n(N) → (C=O) on these regions. (AU)