Structure-based drug target prioritisation and rational drug design for targeting <i>Chlamydia trachomatis</i> eye infections

Sadhasivam, Anupriya; Nagarajan, Hemavathy; Vetrivel, Umashankar

doi:10.1080/07391102.2019.1652691

Cited by 13 publications

(2 citation statements)

References 43 publications

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“…Initially, the ligands were prepared and filtered using standard methods (application of Lipinski rule of five and removal of reactive functional groups) using LigPrep (Schrödinger, LLC, New York, NY). Further, a high-throughput virtual screening (HTVS) protocol of Schrödinger suite was used for virtual screening and scoring of ligands. − …”

Section: Computational Methods and Experimental Sectionmentioning

confidence: 99%

Microsecond Simulation of the Proteoglycan-like Region of Carbonic Anhydrase IX and Design of Chemical Inhibitors Targeting pH Homeostasis in Cancer Cells

et al. 2020

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Carbonic anhydrase IX (CAIX) is a membrane-bound enzyme associated with tumor hypoxia and found to be over expressed in various tumor conditions. Targeting CAIX catalytic activity is proven to be efficient modality in modulating pH homeostasis in cancer cells. Proteoglycan-like (PG) region is unique to CAIX and is proposed to serve as an antenna enhancing the export of protons in conjunction with facilitated efflux of lactate ions via monocarboxylate transporters. Moreover, the PG region is also reported to contribute to the assembly and maturation of focal adhesion links during cellular attachment and dispersion on solid supports. Thus, drug targeting of this region shall efficiently modulate pH homeostasis and cell adhesion in cancer cells. As the PG region is intrinsically disordered, the complete crystal structure is not elucidated. Hence, in this study, we intend to sample the conformational landscape of the PG region at microsecond scale simulation in order to sample the most probable conformations that shall be utilized for structure-based drug design. In addition, the sampled conformations were subjected to high-throughput virtual screening against NCI and Maybridge datasets to identify potential hits based on consensus scoring and validation by molecular dynamics simulation. Further, the identified hits were experimentally validated for efficacy by in vitro and direct enzymatic assays. The results reveal 5-(2-aminoethyl)-1,2,3-benzenetriol to be the most promising hit as it showed significant CAIX inhibition at all levels of in silico and experimental validation.

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Section: Computational Methods and Experimental Sectionmentioning

confidence: 99%

Microsecond Simulation of the Proteoglycan-like Region of Carbonic Anhydrase IX and Design of Chemical Inhibitors Targeting pH Homeostasis in Cancer Cells

et al. 2020

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“…MD simulations are a powerful tool for discovering new inhibitors and investigating drug resistance mechanisms 42,43 . Molecular dynamic simulations of thiazolo [2,3-b] quinazolinone derivatives (5ab, 5aq, and 5bq), reference ligands of both wtEGFR-TKD and EGFR-TKD mutant "TMLR" were done.…”

Section: Molecular Dynamic Simulationsmentioning

confidence: 99%

Molecular Dynamic Simulations and Binding Free Energy Evaluations of Thiazolo-[2,3-b] Quinazolinone Derivatives With wtEGFR-TKD and "TMLR" Mutant EGFR-TKD

Mir

Nayak

2021

Preprint

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Cancer causes innumerable deaths every year globally. Breast cancer and non-small cell lung carcinoma (NSCLC) are the most prevalent worldwide. The epidermal growth factor receptor tyrosine kinases play a pivotal role in manifestations of cellular signals in carcinoma cells and thus are endorsed as therapeutic targets in cancer management. EGFR-TKD is a good option for the treatment of cancer, but the resistance shown by first-generation TKIs leads to hyperphosphorylation, overexpression, and mutations of EGFR-TKD. The new molecular scaffolds of thiazolo-[2,3-b] quinazolinones were evaluated against EGFR-TKD via molecular docking simulations and thereby linked with molecular dynamic simulations to identify the ligand stability with EGFR-TKD’s. The binding energy of thiazolo-[2,3-b] quinazolinones is approximately similar to that of reference molecules found against both wild type wtEGFR-TKD and EGFR-TKD mutant "TMLR" (T790M/L858R) in this study. According to ADMET analysis, thiazolo-[2,3-b] quinazolinone derivatives (5ab, 5aq, and 5bq) are safe. The stability was investigated at an atomistic level by molecular dynamic simulations, and the strength of the bindings was calculated by the molecular mechanics Poisson-Boltzmann surface areas continuum solvation MM-PBSA method. The RMSD, radius of gyration, and SASA trajectories were studied in detail. The ΔGbind generated by heterocyclic 5aq thiazolo-[2,3-b] quinazolinone was found to be -63.723 ± 0.419 kJ/mol against the EGFR-TKD mutant "TMLR" and it was -51.551 ± 0.409 kJ/mol against wtEGFR-TKD. This study concludes that the top ranked complexes 5ab, 5aq, and 5bq with both wild and mutated types of EGFR-TKD corroborate that thiazolo-[2,3-b] quinazolinone derivatives, like the FDA-approved drug erlotinib, may be potent inhibitors of EGFR-TKD for patients with NSCLC.

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Identification of good and bad fragments of tricyclic triazinone analogues as potential PKC-θ inhibitors through SMILES–based QSAR and molecular docking

Kumar

2020

Struct Chem

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Structure-based drug target prioritisation and rational drug design for targeting Chlamydia trachomatis eye infections

Abstract: Fig S1. (a) Snapshot of membrane system of Porin embedded in bilayer lipid of DMPC, and the structure over view and it is seen in cylindrical shape; (b) view of Porin from extracellular side of pore channel.

Cited by 13 publications

References 43 publications

Microsecond Simulation of the Proteoglycan-like Region of Carbonic Anhydrase IX and Design of Chemical Inhibitors Targeting pH Homeostasis in Cancer Cells

Microsecond Simulation of the Proteoglycan-like Region of Carbonic Anhydrase IX and Design of Chemical Inhibitors Targeting pH Homeostasis in Cancer Cells

Molecular Dynamic Simulations and Binding Free Energy Evaluations of Thiazolo-[2,3-b] Quinazolinone Derivatives With wtEGFR-TKD and "TMLR" Mutant EGFR-TKD

Identification of good and bad fragments of tricyclic triazinone analogues as potential PKC-θ inhibitors through SMILES–based QSAR and molecular docking

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