Exploring binding stability of hydroxy-3-(4-hydroxyphenyl)-5-(4-nitrophenyl)-5,5a,7,8,9,9a-hexahydrothiazolo[2,3-b] quinazolin-6-one with T790M/L858R EGFR-TKD

Abstract

Cancer causes innumerable deaths every year globally. Breast cancer and non-small cell lung carcinoma are the most prevalent worldwide. EGFR-TKD is a neoplastic survival therapeutic target in a wide array of carcinoma cells. Various non-specific tyrosine kinase inhibitors lead to hyperphosphorylation and overexpression of EGFR-TKD and further mutations recognise deletion of exon 19. In this work, we study the binding affinity, binding stability, and strength of hydroxy-3-(4-hydroxyphenyl)-5-(4-nitrophenyl)-5,5a,7,8,9,9a-hexahydrothiazolo[2,3-b] quinazolin-6-one with TMLR mutated EGFR-TKD (T790M/L858R). The collective motions, residual mobility, and flexibility of TMLR mutated EGFR-TKD bound with reference and title molecule were calculated by principal component analysis. The meta-state conformations of both the simulated complexes were determined by Gibb’s energy landscape analysis. The binding affinity exhibited by thiazolo-[2,3-b] quinazolinone and the reference molecule was found to be −7.95 ± 0.088 Kcal/mol and −9.13 ± 0.018 kcal/mol with TMLR mutated EGFR-TKD. The alignment of both the docked complexes was done by blosum40 matrix. Similar spatial orientations were exhibited by the synthesised ligand in the binding pocket of TMLR mutated EGFR-TKD, corresponding to the reference ligand. The ligand stability was computed for 100 ns. In addition, the radius of gyration, solvent accessible surface area, hydrogen bonds formed was calculated. The average ΔGbind of thiazolo-[2,3-b] quinazolinone was −41.212 ± 0.834 kJ/mol and for reference ligand −71.938 ± 0.367 kJ/mol, calculated by MM-PBSA. ADMET analysis concludes thiazolo-[2,3-b] quinazolinone derivative is safe. Further research work is encouraged to determine the efficacy of thiazolo-[2,3-b] quinazolinone against in vivo models.

Communicated by Ramaswamy H. Sarma

Keywords:

• TMLR mutated EGFR-TKD
• thiazolo-[2,3-b] quinazolinone derivatives
• molecular dynamic simulations
• MM-PBSA
• Gibbs energy landscape

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

No funding source supports to carry out present findings.

Authors’ contributions

SAM carried out in-silico investigations, Molecular calculations at the atomistic level, and MM-PBSA calculations by using gromacs 5.1.1. SAM prepared the Draft, SAM and BN edited and finalised the Manuscript.

Data availability statement

The data mentioned in this article will be available upon the author’s request. Further, MOE-09 was used and acknowledged, Chem Draw 8.0 was used for sketching the initials, some open-source agreement software such as Open Babel (http://openbabel.org/.) was used for ligand preparations, and VMD accessed at https://www.ks.uiuc.edu/Research/vmd/molecular visualisation program was used for visualisation, displaying, animating, and 3 D diagrams. AutoDock 4 was used for molecular docking simulations: http://autodock.scripps.edu/. Avogadro http://www.avogadro.cc/ were used as molecule editors and visualisers. LigPlot + was used to obtain interactions in 2 D format. https://www.ebi.ac.uk/, and (Molsoft L.L.C www.molsoft.com/mprop/, SWISSadme, http://www.swissadme.ch/, and pkCSM, http://biosig.unimelb.edu/, were used to study ligand toxicities and pharmacokinetic properties of molecular scaffolds selected in this study. Molecular dynamics were carried out by using gromacs 5.1.1 https://gromacs.org. Free software can either be redistributed or modified under the GNU Lesser Public Licence Agreement as provided by free software publications. CGenFF was used to generate topologies at https://cgenff.umaryland.edu/. Free energy calculations were carried out by using gromacs 5.1.1, incorporated with APBS versions 1.2.x, 1.3.x, and all input files are available at https://github.com/RashmiKumari/g_mmpbsa.xmgrace is freely available at (http://plasma-gate.weizmann.ac.il/Grace/) and was used to plot the trajectories obtained from molecular dynamics simulations. The data presented here were not obtained from any published literature and will not violate any future scientific publishing policy terms and conditions.