Computational modeling of novel inhibitory peptides targeting proteoglycan like region of carbonic anhydrase IX and <i>in vitro</i> validation in HeLa cells

John, Arun; Sivashanmugam, Muthukumaran; Natarajan, Sulochana Konerirajapuram; Vetrivel, Umashankar

doi:10.1080/07391102.2019.1623075

Cited by 10 publications

(15 citation statements)

References 47 publications

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“…The protein and ligand complex's binding free energies were calculated by taking 7 snapshots of the last 5 ns MD simulation trajectory and calculating it to be -92.3 kcal/mol using the PRODIGY-LIG method. According to available reports, several plant components can be used effectively as stimulators of non-specific immunity as well as for their curative properties to get rid of infective diseases [22] , [23] . In addition to host and pathogenic macromolecules, designed drugs based on structure and functions have high value in molecular medicine [24] .…”

Section: Resultsmentioning

confidence: 99%

Plant‐Based Natural Bioactive Compounds 2,4‐Ditert‐Butylphenolas: A Potential Candidates Against SARS‐Cov‐2019

Prakash

Selvam

Gayathiri³

et al. 2022

Energy Nexus

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Section: Resultsmentioning

confidence: 99%

Plant‐Based Natural Bioactive Compounds 2,4‐Ditert‐Butylphenolas: A Potential Candidates Against SARS‐Cov‐2019

Prakash

Selvam

Gayathiri³

et al. 2022

Energy Nexus

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“…Further, these cells were maintained in a 5% CO 2 incubator at 37 °C till full confluency is attained and were further used for in vitro experiments. 63 The top hit NSC-298534 (catalog #151564) and acetazolamide (catalog #A6011) were procured from Sigma.…”

Section: ■ Computational Methods and Experimental Section Molecular M...mentioning

confidence: 99%

“…Cell viability (or cell survival) was calculated as (test OD/control OD) × 100. 63 CAIX Functional Assay in HeLa Cells. To perform this assay, intact HeLa cells were suspended in isotonic buffer (130 mM NaCl, 5 mM KCl, and 20 mM Hepes).…”

Section: ■ Computational Methods and Experimental Section Molecular M...mentioning

confidence: 99%

“…Further, 4% paraformaldehyde was used to fix the attached cells to the surface. 63 A Nikon ECLIPSE TS 2 -Fl microscope was used to capture the microphotographs, and the number of attached cells was quantified using NIH Image J software. Based on these images, differential analysis was performed for treated and untreated conditions.…”

Section: ■ Computational Methods and Experimental Section Molecular M...mentioning

confidence: 99%

“…62 Moreover, our group has also shown oligopeptides derived from M75 antibody to be efficient inhibitors of CAIX in HeLa cells. 63 As the proteoglycan-like region is unique to CAIX, it becomes essential to know about its conformational landscape for designing selective inhibitors targeting the tumor cells. Hence, in this study, in order to design chemical moieties targeting the PG-like region, we performed an extensive microsecond scale simulation of the complete PG-like region to sample the conformational landscape.…”

Section: ■ Introductionmentioning

confidence: 99%

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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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Intrinsically disordered features of carbonic anhydrase IX proteoglycan-like domain

Langella

Buonanno

Simone

et al. 2020

Cell. Mol. Life Sci.

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Computational modeling of novel inhibitory peptides targeting proteoglycan like region of carbonic anhydrase IX and in vitro validation in HeLa cells

Cited by 10 publications

References 47 publications

Plant‐Based Natural Bioactive Compounds 2,4‐Ditert‐Butylphenolas: A Potential Candidates Against SARS‐Cov‐2019

Plant‐Based Natural Bioactive Compounds 2,4‐Ditert‐Butylphenolas: A Potential Candidates Against SARS‐Cov‐2019

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

Intrinsically disordered features of carbonic anhydrase IX proteoglycan-like domain

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