Torsional flexibility of undecorated catechol diether compound as potent NNRTI targeting HIV-1 reverse transcriptase.
Conformational adaptation of non-nucleoside reverse transcriptase inhibitor (NNRTI) via torsional flexibility is found to be very significant for targeting human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) mutants. Catechol diether derivative including flexible torsions is new potent NNRTI with picomolar activity. Moreover, this derivative also reveals the good solubility, low toxicity and potent inhibition for HIV-1 mutants. In this study, torsional flexibility of an undecorated catechol diether compound in the binding pocket of wild type and mutants (Y181C and K103N/Y181C) HIV-1 RT is investigated by using QM/MM calculations. From the results, the uracil ring is found to exhibit more flexibility in the NNIBP. On the contrary, potential energy surfaces show that high energy is encountered by changing of the corresponding torsion of the cyanovinyl aryl ring indicating the limitation for torsional flexibility. For pointing out the key interaction for the binding, the residual interaction energies are performed by means of QM calculations. Important attractive interactions through hydrogen bonds between the inhibitor and K102, K/N103, V106, and Y188 are observed. The catechol ring is proposed to be modified in order to strengthen interactions with surrounding amino acids. The results may help for the designing of new potent NNRTIs.
['Somboon|Tuanjai|T|', 'Saparpakorn|Patchreenart|P|', 'Hannongbua|Supa|S|']
D001665:Binding Sites D002396:Catechols D054303:HIV Reverse Transcriptase D006801:Humans D008968:Molecular Conformation D062105:Molecular Docking Simulation D056004:Molecular Dynamics Simulation D015394:Molecular Structure D011485:Protein Binding D021281:Quantitative Structure-Activity Relationship D018894:Reverse Transcriptase Inhibitors
NNRTI HIV-1 RT QM/MM AIDS DFT