Pharmacophore modeling and virtual screening to identify potential RET kinase inhibitors

Shih, Kuei Chung; Shiau, Chung Wai; Chen, Ting Shou; Ko, Ching Huai; Lin, Chih Lung; Lin, Chun Yuan; Hwang, Chrong Shiong; Tang, Chuan Yi; Chen, Wan Ru; Huang, Jui Wen

doi:10.1016/j.bmcl.2011.06.003

Cited by 12 publications

(7 citation statements)

References 68 publications

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“…Then the average RMSD for each protein was computed, and the protein showing the lowest average RMSD was selected for further docking analysis as it could accommodate all the crystal ligands better than the other proteins . The binding energy of the hits with proteins was estimated as negative of CDOCKER interaction energy …”

Section: Methodsmentioning

confidence: 99%

Pharmacophore modeling and molecular dynamics approach to identify putative DNA Gyrase B inhibitors for resistant tuberculosis

Kashyap

Singh

Satpati

et al. 2018

J of Cellular Biochemistry

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One of the major mechanisms followed by the therapeutic agents to target the causative organism of TB, mycobacterium tuberculosis (Mtb), involves disruption of the replication cycle of the pathogen DNA. The process involves two steps that occur simultaneously, ie, breakage and reunion of DNA at gyrase A (GyrA) domain and ATP hydrolysis at gyrase B (GyrB) domain. Current therapy for multi-drug resistant TB involves FDA approved, Fluoroquinolone-based antibiotics, which act by targeting the replication process at GyrA domain. However, resistance against fluoroquinolones due to mutations in the GyrA domain has limited the use of this therapy and shifted the focus of the research community on the GyrB domain. Thus, this study involves in silico designing of chemotherapeutic agents for resistant TB by targeting GyrB domain. In the current study, a pharmacophore model for GyrB domain was generated using reported inhibitors. It was utilized as a query search against three commercial databases to identify GyrB domain inhibitors. Additionally, a qualitative Hip-Hop pharmacophore model for GyrA was also developed on the basis of some marketed fluoroquinolone-based GyrA inhibitors, to remove non-selective gyrase inhibitors obtained in virtual screening. Further, molecular dynamic simulations were carried out to determine the stability of the obtained molecules in complex with both the domains. Finally, Molecular mechanics with generalized Born and surface area solvation score was calculated to determine the binding affinity of obtained molecule with both domains to determine the selectivity of the obtained molecules that resulted in seven putative specific inhibitors of GyrB domain.

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Section: Methodsmentioning

confidence: 99%

Pharmacophore modeling and molecular dynamics approach to identify putative DNA Gyrase B inhibitors for resistant tuberculosis

Kashyap

Singh

Satpati

et al. 2018

J of Cellular Biochemistry

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“…We used three methods to validate the quality of the PhSIA: (i) Fischer’s cross-validation test [23]–[25] (Fischer’s test) was used to assess the confidence of the training set selection; (ii) the partial least squares (PLS) validation method [26]–[29], [39], [40] was used to assess PhSIA prediction quality and accuracy; and (iii) the GH test method [35], [41]–[44] was used to determine the confidence of statistical significance when screening compound databases.…”

Section: Methodsmentioning

confidence: 99%

Development of a Human Dihydroorotate Dehydrogenase (hDHODH) Pharma-Similarity Index Approach with Scaffold-Hopping Strategy for the Design of Novel Potential Inhibitors

et al. 2014

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Human dihydroorotate dehydrogenase (hDHODH) is a class-2 dihydroorotate dehydrogenase. Because it is extensively used by proliferating cells, its inhibition in autoimmune and inflammatory diseases, cancers, and multiple sclerosis is of substantial clinical importance. In this study, we had two aims. The first was to develop an hDHODH pharma-similarity index approach (PhSIA) using integrated molecular dynamics calculations, pharmacophore hypothesis, and comparative molecular similarity index analysis (CoMSIA) contour information techniques. The approach, for the discovery and design of novel inhibitors, was based on 25 diverse known hDHODH inhibitors. Three statistical methods were used to verify the performance of hDHODH PhSIA. Fischer’s cross-validation test provided a 98% confidence level and the goodness of hit (GH) test score was 0.61. The q2, r2, and predictive r2 values were 0.55, 0.97, and 0.92, respectively, for a partial least squares validation method. In our approach, each diverse inhibitor structure could easily be aligned with contour information, and common substructures were unnecessary. For our second aim, we used the proposed approach to design 13 novel hDHODH inhibitors using a scaffold-hopping strategy. Chemical features of the approach were divided into two groups, and the Vitas-M Laboratory fragment was used to create de novo inhibitors. This approach provides a useful tool for the discovery and design of potential inhibitors of hDHODH, and does not require docking analysis; thus, our method can assist medicinal chemists in their efforts to identify novel inhibitors.

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“…The test compound was docked into the protein active site using the CHARMmbased docking tool of the CDOCKER program. The binding energy of the hits with proteins was estimated as negative of the CDOCKER interaction energy [32].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

Anticonvulsive Effects of Chondroitin Sulfate on Pilocarpine and Pentylenetetrazole Induced Epileptogenesis in Mice

Singh

et al. 2021

Molecules

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Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to the extracellular matrix, regulates the intracellular positive ion concentration, and maintains the hypersynchronous epileptiform activity. Therefore, the present study hypothesized an antiepileptic potential of chondroitin sulfate (CS) in pentylenetetrazole-induced kindled epilepsy and pilocarpine-induced status epilepticus in mice. Levels of various oxidative stress markers and inflammatory mediators were estimated in the brain tissue homogenate of mice, and histopathological changes were evaluated. Treatment with valproate (110 mg/kg; i.p.) as a standard drug and chondroitin sulfate (100 & 200 mg/kg, p.o.) significantly (p < 0.01) and dose-dependently prevented the severity of kindled and spontaneous recurrent seizures in mice. Additionally, chondroitin sulfate showed its antioxidant potential by restoring the various biochemical levels and anti-inflammatory properties by reducing NF-kB levels and pro-inflammatory mediators like TNF-alpha, IL-1β, and IL-6, indicating the neuroprotective effect as well as the suppressed levels of caspase-3, which indicated a neuroprotective treatment strategy in epilepsy. The proteoglycan chondroitin sulfate restores the normal physiology and configuration of the neuronal tissue. Further, the molecular docking of chondroitin sulfate at the active pockets of TNF-alpha, IL-1β, and IL-6 showed excellent interactions with critical amino acid residues. In conclusion, the present work provides preclinical evidence of chondroitin sulfate as a new therapeutic approach in attenuating and preventing seizures with a better understanding of the mechanism of alteration in ECM changes influencing abnormal neuronal activities.

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Pharmacophore modeling and virtual screening to identify potential RET kinase inhibitors

Cited by 12 publications

References 68 publications

Pharmacophore modeling and molecular dynamics approach to identify putative DNA Gyrase B inhibitors for resistant tuberculosis

Pharmacophore modeling and molecular dynamics approach to identify putative DNA Gyrase B inhibitors for resistant tuberculosis

Development of a Human Dihydroorotate Dehydrogenase (hDHODH) Pharma-Similarity Index Approach with Scaffold-Hopping Strategy for the Design of Novel Potential Inhibitors

Anticonvulsive Effects of Chondroitin Sulfate on Pilocarpine and Pentylenetetrazole Induced Epileptogenesis in Mice

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