BREED based de novo hybridization approach: generating novel T790M/C797S-EGFR tyrosine kinase inhibitors to overcome the problem of mutation and resistance in non small cell lung cancer (NSCLC)

Patel, Harun; Shaikh, Matin; Ahmad, Iqrar; Lokwani, Deepak K.; Surana, Sanjay J.

doi:10.1080/07391102.2020.1754918

Cited by 27 publications

(12 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On March 30, 2017, the US Food and Drug Administration (FDA) conceded regular approval to Osimertinib (AZD9291) for the management of patients with metastatic “EGFR-T790M Non-Small Cell Lung Cancer (NSCLC)”. , The FDA-approved drug Osimertinib is at the forefront for the treatment of NSCLC patients (Figure ). − However, a significant proportion of Osimertinib-treated patients developed the EGFR kinase tertiary cystein 797 to serine 797 (C797S) mutation by the loss of covalent binding with the Cys797 residue, which renders a resistance to all the existing drugs. , Additional studies with mutant cell lines have shown that the allelic context of the activating gatekeeper and C797S mutations affects the sensitivity of three generations of EGFR inhibitors, with no epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) alone or in combination able to suppress activity when the mutation is in the cis -form. − These data suggest that there is a pressing need for drugs that can overcome the ternary mutation (L858R/T790M/C797S EGFR) obstacle in NSCLC . The crystallographic structure of C797S-EGFR revealed that the C797S mutation has no effect on the EGFR kinase’s structure or function but does increase the degree of local hydrophilicity around residue 797 (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer

et al. 2021

Self Cite

View full text Add to dashboard Cite

The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction.

show abstract

Section: Introductionmentioning

confidence: 99%

Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Five different proteins with five different pesticides complex were subjected to MD simulation for 100 ns. The stability of the protein-ligand complex was determined ( Patel et al, 2021 ) by comparing the RMSD and RMSF values of the unbound protein structure. In MD simulations, the RMSD parameter is used to evaluate the coherence and flexibility of proteins as well as to keep track of the separation between their atoms and backbones ( Sargsyan et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…In order to relax the system to the lowest local energy, minimization tasks were carried out. Next, this model system was run to MD simulation steps using the OPLS 2005 force field parameter ( Lee et al, 2021 ; Patel et al, 2021 ). The MD simulation was performed up to 100 ns using the NPT ensemble (isothermal-isobaric ensemble, constant temperature, constant pressure, and constant number of particles) at 300 K temperature and 1.013 bar pressure ( Jorgensen et al, 1996 ; Lee et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…For controlling temperature and pressure, the Noose-Hover chain thermostat algorithm and the Martyna-Tobias-Klein barostat algorithm were employed, respectively. The particle mesh Ewald method was used to measure long-range electrostatic interactions, while the other parameters were left at their default values ( Patel et al, 2021 ). The behavior and interactions between the ligands and protein were examined using the Simulation Interaction Diagram tool.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Unveiling chlorpyrifos mineralizing and tomato plant-growth activities of Enterobacter sp. strain HSTU-ASh6 using biochemical tests, field experiments, genomics, and in silico analyses

et al. 2022

Self Cite

View full text Add to dashboard Cite

The chlorpyrifos-mineralizing rice root endophyte Enterobacter sp. HSTU-ASh6 strain was identified, which enormously enhanced the growth of tomato plant under epiphytic conditions. The strain solubilizes phosphate and grew in nitrogen-free Jensen’s medium. It secreted indole acetic acid (IAA; 4.8 mg/mL) and ACC deaminase (0.0076 μg/mL/h) and hydrolyzed chlorpyrifos phosphodiester bonds into 3,5,6-trichloro-2-pyridinol and diethyl methyl-monophosphate, which was confirmed by Gas Chromatography – Tandem Mass Spectrometry (GC–MS/MS) analysis. In vitro and in silico (ANI, DDH, housekeeping genes and whole genome phylogenetic tree, and genome comparison) analyses confirmed that the strain belonged to a new species of Enterobacter. The annotated genome of strain HSTU-ASh6 revealed a sets of nitrogen-fixing, siderophore, acdS, and IAA producing, stress tolerance, phosphate metabolizing, and pesticide-degrading genes. The 3D structure of 28 potential model proteins that can degrade pesticides was validated, and virtual screening using 105 different pesticides revealed that the proteins exhibit strong catalytic interaction with organophosphorus pesticides. Selected docked complexes such as α/β hydrolase–crotoxyphos, carboxylesterase–coumaphos, α/β hydrolase–cypermethrin, α/β hydrolase–diazinon, and amidohydrolase–chlorpyrifos meet their catalytic triads in visualization, which showed stability in molecular dynamics simulation up to 100 ns. The foliar application of Enterobacter sp. strain HSTU-ASh6 on tomato plants significantly improved their growth and development at vegetative and reproductive stages in fields, resulting in fresh weight and dry weight was 1.8–2.0-fold and 1.3–1.6-fold higher in where urea application was cut by 70%, respectively. Therefore, the newly discovered chlorpyrifos-degrading species Enterobacter sp. HSTU-ASh6 could be used as a smart biofertilizer component for sustainable tomato cultivation.

show abstract

“…A total of 100 ns simulations were run, during which 1000 trajectories were recorded. Finally, the Simulation Interaction Diagram (SID) tool was used to examine the MD simulation trajectory [ 63 , 64 , 65 ]. The interaction energies between the protein and the ligand poses were computed using the MM-GBSA (molecular merchandised generalized-born/surface area) method implemented by Schrodinger [ 23 , 24 , 25 ].…”

Section: Methodsmentioning

confidence: 99%

Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations

Zrieq

Ahmad

Snoussi

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.

show abstract

BREED based de novo hybridization approach: generating novel T790M/C797S-EGFR tyrosine kinase inhibitors to overcome the problem of mutation and resistance in non small cell lung cancer (NSCLC)

Cited by 27 publications

References 37 publications

Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer

Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer

Unveiling chlorpyrifos mineralizing and tomato plant-growth activities of Enterobacter sp. strain HSTU-ASh6 using biochemical tests, field experiments, genomics, and in silico analyses

Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations

Contact Info

Product

Resources

About