The reverse transcriptase (RT) of the human immunodeficiency virus type-1 (HIV-1) is the essential enzyme converting the single-stranded viral RNA genome into double-stranded proviral DNA. Non-nucleoside reversetranscriptase inhibitors (NNRTIs) are interesting for developing novel potent inhibitors because of their high sensitivity and high specificity. However, there occurs rapid development of drug resistance caused by mutation. Nowadays, novel NNRTIs influencing the mutation of HIV-1 RT are challenging. In this study, some new NNRTIs are investigated as follows; (1) A series of NNRTIs, pyrazinones, are found to active against wild-type HIV-1 RT and some of them are also active against mutant HIV-1 RT. Therefore, the specific binding mode of pyrazinones to HIV-1 RT is needed for suggesting the design of novel potent NNRTIs active against both wild and mutant HIV-1 RT. The combination of molecular docking, 3D-QSAR and quantum chemical calculations has been applied. The docked conformation of each pyrazinone is selected to construct COMFA and CoMSIA models. Both models suggest that the substituent at pamionphenyl position prefers the steric bulky, electron-withdrawing, H-acceptor, and disfavored hydrophobic groups. In addition, the obtained interaction energies between compound no. 9 and the binding pocket by quantum chemical calculations show the important attractive interactions with Glu138(B). (2) The interaction of a HIV-1 reverse transcriptase inhibitor, S-3-ethyl-7-fluoro-4- isopropoxy-carbonyl-3,4-dihydro-quinoxalin-2(1H)-one (GW420867X), with the wild type HIV-1 RT binding pocket has been analyzed by using quantum chemical calculations. Interaction energies between GW420867X and the surrounding amino acids are calculated by B3LYP and MP2 methods using 6-31G(d), 6-31G(d,p), 6-311G(d), and 6-311G(d,p) basis sets with BSSE. Particularly, the interaction energy with Lys101, recognized as the most important amino acid for the binding of the inhibitor, was calculated using various models, to evaluate which terminating residues have to be taken into account. The optimal results confirmed that GW420867X forms the most important attractive interaction with Lys101 via a hydrogen bond between the ammonium group and the backbone atoms of Lys101. The results are powerful to describe the binding mode of NNRTIs and suggest the design of new potent NNRTIs.