Rational Discovery of Novel Squalene Synthase Inhibitors through Pharmacophore Modelling

Chokshi, Avani; Chhabria, Mahesh T.; Desai, Pritesh R.

doi:10.2174/1573409914666180507143024

Cited by 5 publications

(3 citation statements)

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“…In wild- syn model, MTP of PLP- syn was set as the center to determine amino acid residues within 3 Å. Then, the candidates were carried out with virtual mutation and screening by (binding) mutation energies. − The top five stabilizing mutants Y31H, H128K, H128R, Y31K, and Y31R were formed by site-directed mutagenesis (Table S2). The other mutants, such as H128N and Y31F, were also constructed according to structure analysis.…”

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confidence: 99%

Construction of a Highly Diastereoselective Aldol Reaction System with l-Threonine Aldolase by Computer-Assisted Rational Molecular Modification and Medium Engineering

Zheng

Chen

Wang³

et al. 2020

Org. Lett.

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Diastereoselectivity of l-threonine aldolase (LTA) was determined by paths of aldehydes attacking a pyridoxal phosphate–glycine complex. Thus, strategies of enhancing the syn path and blocking the anti path were performed to modify LTA. A mutant (Y31H/N305R) was constructed with a substrate preference increase from 3.32 to 42.04. Medium engineering was investigated. Consequently, the de value of l-syn-3-[4-(methylsulfonyl)phenylserine] reached 93.1% (87.2%conv). The study clarified the factors affecting diastereoselectivity of LTA and provided a theorem for rational modification of LTA’s diastereoselectivity.

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confidence: 99%

Construction of a Highly Diastereoselective Aldol Reaction System with l-Threonine Aldolase by Computer-Assisted Rational Molecular Modification and Medium Engineering

Zheng

Chen

Wang³

et al. 2020

Org. Lett.

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“…After removing water, adding polar hydrogen atoms, and extracting the ligand structureby using Pymol software, docking validation was completed by Autodock software (Version1.1.2) [ 22 ]. The binding activity between the targets and the active ingredients was evaluated and visualized using Discovery Studio 2020 [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

Integrating network pharmacology and experimental verification strategies to reveal the active ingredients and molecular mechanism of Tenghuang Jiangu Capsule against osteoporosis

Li,

Tang,

et al. 2023

Heliyon

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“…The weight cost and the con guration cost are also valuable in the validation of the hypotheses. The con guration cost indicates the entropy of the generated model and it should be lower than 17 [45][46][47] .…”

Section: Pharmacophore Modeling and Validation Parametersmentioning

confidence: 99%

1,3,5-Triazine Based Hydroxamic Acid Analogues as HDAC Inhibitors: Integrated Modelling by 3D QSAR, Hypogen Pharmacophore Based Virtual Screening and Molecular Dynamic Simulation Studies

Patel

Kurmi

Gupta

et al. 2023

Preprint

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Histone deacetylase (HDAC) is one of the therapeutically relevant target for the treatment of various types of cancer. To establish a correlation between biological potency and their structural features using a combined approach of Hypogen pharmacophore and five different 3D QSAR models. Hypogen model (Hypo1) for HDAC inhibitors was developed on the basis of existing one, having good correlation coefficient (R= 0.76), lowest root mean square deviation (RMSD) of 0.91, maximum fit value of 9.77 and highest cost difference value of 66.86. Quality validation of Hypo1 through cost analyses, test set prediction and Fischer’s randomization test suggested that the model can reliably detect HDAC inhibitors. The five different 3D QSAR models i.e., Recursive Partitioning Classification Model (pkRP model), Multiple Linear Regression (MLR) analysis, Partial Least Square (PLS), Genetic Function Approximation (GFA) models and Field based (or Grid Based) QSAR models were created and validated. Furthermore, top scored compounds were filtered through the virtual screening and after that, molecular dynamic (MD) simulation and MM-GBSA studies were used to validate the stability, binding energy and electrostatics of best HDAC receptor-ligand complex. The outcome of findings indicated that the best Field based model has R2=0.970and Q2=0.842, the best pkRP model has R2= 0.883 and Q2= 0.813, the best PLS model has R2= 0.856 and Q2= 0.746,the best MLR model has R2= 0.766 and Q2= 0.752, and the best GFA model has R2= 0.706 and Q2= 0.663. Cross-validated coefficient, (rcv2) of 0.968, 0.827, 0.743, 0.810 and 0.552 was found for Field/Grid based, pkRP, MLR, PLS and GFA model, respectively indicating the satisfied correlativity and prediction. The outcome of these studies will be a focal paradigm for designing of novel lead molecules as HDAC inhibitors with improved anticancer activity.

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Rational Discovery of Novel Squalene Synthase Inhibitors through Pharmacophore Modelling

Abstract: The best scoring molecule, compound 67 showed 53% inhibition of the human Squalene synthase enzyme, isolated from the cell lysates of Human Hepatoma Cell Line, at a dose of 10 mcg with an IC50 value of 9.43 µm.

Cited by 5 publications

References 0 publications

Construction of a Highly Diastereoselective Aldol Reaction System with l-Threonine Aldolase by Computer-Assisted Rational Molecular Modification and Medium Engineering

Construction of a Highly Diastereoselective Aldol Reaction System with l-Threonine Aldolase by Computer-Assisted Rational Molecular Modification and Medium Engineering

Integrating network pharmacology and experimental verification strategies to reveal the active ingredients and molecular mechanism of Tenghuang Jiangu Capsule against osteoporosis

1,3,5-Triazine Based Hydroxamic Acid Analogues as HDAC Inhibitors: Integrated Modelling by 3D QSAR, Hypogen Pharmacophore Based Virtual Screening and Molecular Dynamic Simulation Studies

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