3D QSAR pharmacophore-based virtual screening and molecular docking studies to identify novel matrix metalloproteinase 12 inhibitors

Singh, Udghosh; Gangwal, Rahul P.; Prajapati, Rameshwar; Dhoke, Gaurao V.; Sangamwar, Abhay T.

doi:10.1080/08927022.2012.731506

Cited by 14 publications

(6 citation statements)

References 33 publications

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“…Out of these, GH and E-value are the two major parameters, playing a significant role in identifying capability of the generated pharmacophore hypothesis. [ 50 ]…”

Section: Methodsmentioning

confidence: 99%

Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches

et al. 2018

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Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for Type 2 diabetes due to its specific role as a negative regulator of insulin signaling pathways. Discovery of active site directed PTP1B inhibitors is very challenging due to highly conserved nature of the active site and multiple charge requirements of the ligands, which makes them non-selective and non-permeable. Identification of the PTP1B allosteric site has opened up new avenues for discovering potent and selective ligands for therapeutic intervention. Interactions made by potent allosteric inhibitor in the presence of PTP1B were studied using Molecular Dynamics (MD). Computationally optimized models were used to build separate pharmacophore models of PTP1B and TCPTP, respectively. Based on the nature of interactions the target residues offered, a receptor based pharmacophore was developed. The pharmacophore considering conformational flexibility of the residues was used for the development of pharmacophore hypothesis to identify potentially active inhibitors by screening large compound databases. Two pharmacophore were successively used in the virtual screening protocol to identify potential selective and permeable inhibitors of PTP1B. Allosteric inhibition mechanism of these molecules was established using molecular docking and MD methods. The geometrical criteria values confirmed their ability to stabilize PTP1B in an open conformation. 23 molecules that were identified as potential inhibitors were screened for PTP1B inhibitory activity. After screening, 10 molecules which have good permeability values were identified as potential inhibitors of PTP1B. This study confirms that selective and permeable inhibitors can be identified by targeting allosteric site of PTP1B.

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“…Out of these, GH and E-value are the two major parameters, playing a significant role in identifying capability of the generated pharmacophore hypothesis. [ 50 ]…”

Section: Methodsmentioning

confidence: 99%

Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches

et al. 2018

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“…A c c e p t e d M a n u s c r i p t 10 Where D, A, Ht and TP represent the total number of compounds of the database, total number of actives, total number of hits and total number of true actives in the hits, respectively [20]. Hypo1_PDE4B and…”

Section: Pharmacophore Model Validationmentioning

confidence: 99%

“…During this process, maximum number of conformers was set to 255 with 4.0 kcal/mol as energy cutoff, and all other parameters were set to default [20]. Pharmacophore models were then generated using the HypoGen algorithm implemented in Accelrys Discovery Studio2.5 (DS2.5) [21].…”

Section: Data Setsmentioning

confidence: 99%

Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors

Gangwal

Damre

Das

et al. 2015

Journal of Molecular Graphics and Modelling

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“…34 active cytochrome bc1 inhibitors were included in the database to calculate various statistical parameters such as accuracy, precision, sensitivity, specificity, goodness of hit score (GH), and enrichment factor (E value). Out of these, GH and E value are the two major parameters, playing significant role in identifying capability of the generated pharmacophore hypothesis [21].…”

Section: Validation Of Pharmacophore Modelmentioning

confidence: 99%

Structure-Based Virtual Screening and Molecular Dynamic Simulation Studies to Identify Novel Cytochrome bc1 Inhibitors as Antimalarial Agents

Gangwal

Dhoke

Damre

et al. 2013

Journal of Computational Medicine

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Cytochromebc1(EC 1.10.2.2,bc1) is an essential component of the cellular respiratory chain, which catalyzes electron transfer from quinol to cytochrome c and concomitantly the translocation of protons across the membrane. It has been identified as a promising target in malaria parasites. The structure-based pharmacophore modelling and molecular dynamic simulation approach have been employed to identify novel inhibitors of cytochromebc1. The best structure-based pharmacophore hypothesis (Hypo1) consists of one hydrogen bond acceptor (HBA), one general hydrophobic (HY), and two hydrophobic aromatic features (HYAr). Further, hydrogen interactions and hydrophobic interactions of known potent inhibitors with cytochromebc1were compared with Hypo1, which showed that the Hypo1 has good predictive ability. The validated Hypo1 was used to screen the chemical databases. The hits obtained were subsequently subjected to the molecular docking analysis to identify false-positive hits. Moreover, the molecular docking results were further validated by molecular dynamics simulations. Binding-free energy analysis using MM-GBSA method reveals that the van der Waals interactions and the electrostatic energy provide the basis for favorable absolute free energy of the complex. The five virtual hits were identified as possible candidates for the designing of potent cytochromebc1inhibitors.

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3D QSAR pharmacophore-based virtual screening and molecular docking studies to identify novel matrix metalloproteinase 12 inhibitors

Cited by 14 publications

References 33 publications

Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches

Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches

Structure based virtual screening to identify selective phosphodiesterase 4B inhibitors

Structure-Based Virtual Screening and Molecular Dynamic Simulation Studies to Identify Novel Cytochrome bc1 Inhibitors as Antimalarial Agents

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