Insight into the Effect of Inhibitor Resistant S130G Mutant on Physico-Chemical Properties of SHV Type Beta-Lactamase: A Molecular Dynamics Study

Baig, Mohammad Hassan; Sudhakar, D.; Kalaiarasan, P.; Subbarao, Naidu; Wadhawa, Gulshan; Lohani, Mohtashim; Khan, Mohammad Kalim Ahmad; Khan, Asad

doi:10.1371/journal.pone.0112456

Cited by 67 publications

(36 citation statements)

References 38 publications

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“…We also examined the radius of gyration and solvent accessibility of surface area analysis to determine that how the unfolding of the mutant protein structure reduces the surface area solubility and how the protein activity is reduced. Higher the Rg value indicates lower the stability [40]. We observed that native structure has less Rg range as compare to the mutants which proved that both mutations Y127H and G334A decrease the stability of protein and hence reduce the protein functionality.…”

Section: Discussionmentioning

confidence: 58%

Computational analysis of functional single nucleotide polymorphisms associated with SLC26A4 gene

et al. 2020

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Single Nucleotide Polymorphisms (SNPs) are the most common candidate mutations in human beings that play a vital role in the genetic basis of certain diseases. Previous studies revealed that Solute Carrier Family 26 Member 4 (SLC26A4) being an essential gene of the multi-faceted transporter family SLC26 facilitates reflexive movement of Iodide into follicular lumen through apical membrane of thyrocyte. SLC26A4 gene encodes Pendred protein, a membrane glycoprotein, highly hydrophobic in nature, present at the apical membrane of thyrocyte functioning as transporter of iodide for thyroid cells. A minor genetic variation in SLC26A4 can cause Pendred syndrome, a syndrome associated with thyroid glands and deafness. In this study, we performed in-silico analysis of 674 missense SNPs of SLC26A4 using different computational platforms. The bunch of tools including SNPNEXUS, SNAP-2, PhD-SNP, SNPs&GO, I-Mutant, ConSurf, and ModPred were used to predict 23 highly confident damaging and disease causing nsSNPs (G209V,

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Section: Discussionmentioning

confidence: 58%

Computational analysis of functional single nucleotide polymorphisms associated with SLC26A4 gene

et al. 2020

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“…The key signaling proteins PI3K, AKT, and mTOR are used in the current study for designing inhibitors as anticancer agents. Various computational drug‐design approaches, including molecular docking and dynamic simulation, have been successfully used for the identification of better drug candidates . The set of compounds used for screening against the 3 proteins includes naphthoquinones or naphthoquinone analogs.…”

Section: Introductionmentioning

confidence: 99%

Virtual screening of naphthoquinone analogs for potent inhibitors against the cancer‐signaling PI3K/AKT/mTOR pathway

Rehan

Bajouh

2018

J of Cellular Biochemistry

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The PI3K/AKT/mTOR pathway is one of the most commonly disrupted signaling pathways that plays a role in the development and pathogenicity of multiple cancers. Therefore, the critical proteins of this pathway have been targeted for anticancer therapy. The scientific community has increasingly been realizing the anti‐cancer therapeutic potential of naphthoquinone analogs. These compounds constitute a major class of diverse sets of plant metabolites, which include various natural products and synthetic compounds with proven anticancer activity. The current study involved structural computational biology approaches to explore compounds from a diverse pool of naphthoquinone analogs that can inhibit key cancer‐signaling proteins phosphoinositide 3‐kinase (PI3K), protein kinase B, PKB (AKT), and mammalian target of rapamycin (mTOR). The novel compound identified commonly among the top 10 dock score lists of PI3K, AKT, and mTOR was selected for further study and proposed as a potential inhibitor of the 3 cancer‐signaling proteins and an anticancer agent. Further, to check the docking accuracy and potential of the compound, post docking analyses, namely, binding comparison with the native ligand, the role of the interacting residue role in binding, predicted binding energy and dissociation constant calculations, etc., were performed. All these measures showed good‐quality binding, and thus provide weight to our prediction of the novel compound as a pan PI3K/AKT/mTOR inhibitor and an anticancer agent. Finally, to compare the binding and similarity in the active sites of the 3 protein kinases, a ligand‐based active site alignment was performed and analyzed. Thus, the study proposed a novel naphthoquinone analog as a potential anticancer drug, and provided comparative structural insight into its binding to the 3 protein kinases.

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“…V‐rescale temperature coupling and Parrinello‐Rahman pressure coupling were used to keep the system in a stable environment (300 k, 1 bar), and the coupling constants were set to 0.1 and 2.0 ps for temperature and pressure, respectively . The Partial Mesh Ewald (PME) algorithm . was employed for electrostatic and Van der Waals interactions; cut‐off distance for the short‐range VdW (rvdw) was set to 1.4 nm, where Coulomb cut‐off (r coulomb) and a neighbor list (rlist) were fixed at 0.9 nm.…”

Section: Methodsmentioning

confidence: 99%

Identification of novel inhibitors against UDP‐galactopyranose mutase to combat leishmaniasis

Kashif

Tabrez

Husein

et al. 2017

J of Cellular Biochemistry

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Leishmania, a protozoan parasite that causes leishmaniasis, affects 1-2 million people every year worldwide. Leishmaniasis is a vector born disease and characterized by a diverse group of clinical syndromes. Current treatment is limited because of drug resistance, high cost, poor safety, and low efficacy. The urgent need for potent agents against Leishmania has led to significant advances in the development of novel antileishmanial drugs. β-galactofuranose (β-Galf) is an important component of Leishmanial cell surface matrix and plays a critical role in the pathogenesis of parasite. UDP-galactopyranose mutase (UGM) converts UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf) which acts as the precursor for β-Galf synthesis. Due to its absence in human, this enzyme is selected as the potential target in search of new antileishmanial drugs. Three dimensional protein structure model of Leishmania major UGM (LmUGM) has been homology modeled using Trypanosoma cruzi UGM (TcUGM) as a template. The stereochemistry was validated further. We selected already reported active compounds from PubChem database to target the LmUGM. Three compounds (6064500, 44570814, and 6158954) among the top hit occupied the UDP binding site of UGM suggested to work as a possible inhibitor for it. In vitro antileishmanial activity assay was performed with the top ranked inhibitor, 6064500. The 6064500 molecule has inhibited the growth of Leishmania donovani promastigotes significantly. Further, at similar concentrations it has exhibited significantly lesser toxicity than standard drug miltefosine hydrate in mammalian cells.

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Insight into the Effect of Inhibitor Resistant S130G Mutant on Physico-Chemical Properties of SHV Type Beta-Lactamase: A Molecular Dynamics Study

Cited by 67 publications

References 38 publications

Computational analysis of functional single nucleotide polymorphisms associated with SLC26A4 gene

Computational analysis of functional single nucleotide polymorphisms associated with SLC26A4 gene

Virtual screening of naphthoquinone analogs for potent inhibitors against the cancer‐signaling PI3K/AKT/mTOR pathway

Identification of novel inhibitors against UDP‐galactopyranose mutase to combat leishmaniasis

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