In silico design of novel quinazoline-based compounds as potential Mycobacterium tuberculosis PknB inhibitors through 2D and 3D-QSAR, molecular dynamics simulations combined with pharmacokinetic predictions

Chayanin Hanwarinroj, Paptawan Thongdee, Darunee Sukchit, Somjintana Taveepanich, Auradee Punkvang, Pharit Kamsri, Patchreenart Saparpakorn, Sombat Ketrat Ketrat, Supa Hannongbua, Khomson Suttisintong, Prasat Kittakoop, James Spencer, Adrian J Mulholland, Pornpan Pungpo*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Serine/threonine protein kinase B (PknB) is essential to Mycobacterium tuberculosis (M. tuberculosis) cell division and metabolism and a potential anti-tuberculosis drug target. Here we apply Hologram Quantitative Structure Activity Relationship (HQSAR) and three-dimensional QSAR (Comparative Molecular Similarity Indices Analysis (CoMSIA)) methods to investigate structural requirements for PknB inhibition by a series of previously described quinazoline derivatives. PknB binding of quinazolines was evaluated by molecular dynamics (MD) simulations of the catalytic domain and binding energies calculated by Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) methods. Evaluation of a training set against experimental data showed both HQSAR and CoMSIA models to reliably predict quinazoline binding to PknB, and identified the quinazoline core and overall hydrophobicity as the major contributors to affinity. Calculated binding energies also agreed with experiment, and MD simulations identified hydrogen bonds to Glu93 and Val95, and hydrophobic interactions with Gly18, Phe19, Gly20, Val25, Thr99 and Met155, as crucial to PknB binding. Based on these results, additional quinazolines were designed and evaluated in silico, with HQSAR and CoMSIA models identifying sixteen compounds, with predicted PknB binding superior to the template, whose activity spectra and physicochemical, pharmacokinetic, and anti-M. tuberculosis properties were assessed. Compound, D060, bearing additional ortho- and meta-methyl groups on its R2 substituent, was superior to template regarding PknB inhibition and % caseum fraction unbound, and equivalent in other aspects, although predictions identified hepatotoxicity as a likely issue with the quinazoline series. These data provide a structural basis for rational design of quinazoline derivatives with more potent PknB inhibitory activity as candidate anti-tuberculosis agents.
Original languageEnglish
Article number108231
Number of pages19
JournalJournal of Molecular Graphics and Modelling
Volume115
Early online date28 May 2022
DOIs
Publication statusPublished - 3 Jun 2022

Bibliographical note

Funding Information:
This research was supported by the Thailand Research Fund (RSA5980057) and the Thailand Graduate Institute of Science and Technology (TGIST) (SCA-CO-2560-4375TH to C. Hanwarinroj). We would like to thank the center of excellence for innovation in chemistry (PERCH-CIC), Faculty of Science, Ubon Ratchathani University, Faculty of Science, Nakhon Phanom University, Faculty of Science, Kasetsart University, and the University of Bristol for their support and facilities. We acknowledge UK EPSRC funding via BristolBridge (grant number EP/M027546/1) and CCP-BioSim (grant number EP/M022609/1). The National Electronics and Computer Technology Center (NECTEC) and the National Nanotechnology Center (NANOTEC) are also gratefully acknowledged for supporting this research.

Funding Information:
This research was supported by the Thailand Research Fund ( RSA5980057 ) and the Thailand Graduate Institute of Science and Technology (TGIST) ( SCA-CO-2560-4375TH to C. Hanwarinroj). We would like to thank the center of excellence for innovation in chemistry (PERCH-CIC) , Faculty of Science, Ubon Ratchathani University , Faculty of Science, Nakhon Phanom University, Faculty of Science, Kasetsart University , and the University of Bristol for their support and facilities. We acknowledge UK EPSRC funding via BristolBridge (grant number EP/M027546/1 ) and CCP-BioSim (grant number EP/M022609/1 ). The National Electronics and Computer Technology Center (NECTEC) and the National Nanotechnology Center (NANOTEC) are also gratefully acknowledged for supporting this research.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • Tuberculosis
  • PknB inhibitors
  • HQSAR
  • 3D-QSAR CoMSIA
  • Binding energy
  • MD simulations

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