Torsional flexibility of undecorated catechol diether compound as potent NNRTI targeting HIV-1 reverse transcriptase

Tuanjai Somboon; Patchreenart Saparpakorn; Supa Hannongbua

doi:10.1016/j.jmgm.2018.10.026

Torsional flexibility of undecorated catechol diether compound as potent NNRTI targeting HIV-1 reverse transcriptase

J Mol Graph Model. 2019 Jan:86:286-297. doi: 10.1016/j.jmgm.2018.10.026. Epub 2018 Oct 30.

Authors

Tuanjai Somboon¹, Patchreenart Saparpakorn², Supa Hannongbua³

Affiliations

¹ Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand.
² Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand; Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok, 10900, Thailand. Electronic address: fscipnsk@ku.ac.th.
³ Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand; Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok, 10900, Thailand. Electronic address: fscisph@ku.ac.th.

PMID: 30445408
DOI: 10.1016/j.jmgm.2018.10.026

Abstract

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.

Keywords: AIDS; DFT; HIV-1 RT; NNRTI; QM/MM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Catechols / chemistry*
Catechols / pharmacology*
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / chemistry*
Humans
Molecular Conformation
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Protein Binding
Quantitative Structure-Activity Relationship
Reverse Transcriptase Inhibitors / chemistry*
Reverse Transcriptase Inhibitors / pharmacology*

Substances

Catechols
Reverse Transcriptase Inhibitors
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase