ChemInform Abstract: Antimitotic Diterpenes from Erythropodium caribaeorum Test Pharmacophore Models for Microtubule Stabilization.

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

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Prediction of Drug-Drug Interactions Related to Inhibition or Induction of Drug-Metabolizing Enzymes

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190123160406 ◽

2019 ◽

Vol 19 (5) ◽

pp. 319-336 ◽

Cited By ~ 8

Author(s):

Alexander V. Dmitriev ◽

Alexey A. Lagunin ◽

Dmitry А. Karasev ◽

Anastasia V. Rudik ◽

Pavel V. Pogodin ◽

...

Keyword(s):

In Silico ◽

Computational Models ◽

Field Analysis ◽

Pharmaceutical Chemistry ◽

Sources Of Information ◽

Metabolizing Enzymes ◽

Physiologically Based Pharmacokinetic ◽

Pharmacophore Models ◽

Drug Metabolising Enzymes ◽

In Silico Methods

Drug-drug interaction (DDI) is the phenomenon of alteration of the pharmacological activity of a drug(s) when another drug(s) is co-administered in cases of so-called polypharmacy. There are three types of DDIs: pharmacokinetic (PK), pharmacodynamic, and pharmaceutical. PK is the most frequent type of DDI, which often appears as a result of the inhibition or induction of drug-metabolising enzymes (DME). In this review, we summarise in silico methods that may be applied for the prediction of the inhibition or induction of DMEs and describe appropriate computational methods for DDI prediction, showing the current situation and perspectives of these approaches in medicinal and pharmaceutical chemistry. We review sources of information on DDI, which can be used in pharmaceutical investigations and medicinal practice and/or for the creation of computational models. The problem of the inaccuracy and redundancy of these data are discussed. We provide information on the state-of-the-art physiologically- based pharmacokinetic modelling (PBPK) approaches and DME-based in silico methods. In the section on ligand-based methods, we describe pharmacophore models, molecular field analysis, quantitative structure-activity relationships (QSAR), and similarity analysis applied to the prediction of DDI related to the inhibition or induction of DME. In conclusion, we discuss the problems of DDI severity assessment, mention factors that influence severity, and highlight the issues, perspectives and practical using of in silico methods.

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Combiphore (Structure and Ligand Based Pharmacophore) - Approach for the Design of GPR40 Modulators in the Management of Diabetes

Current Drug Discovery Technologies ◽

10.2174/1570163815666181008165822 ◽

2020 ◽

Vol 17 (2) ◽

pp. 233-247

Author(s):

Krishna A. Gajjar ◽

Anuradha K. Gajjar

Keyword(s):

Molecular Docking ◽

Structural Information ◽

Docking Studies ◽

Structural Motif ◽

Roc Curve Analysis ◽

Ligand Complex ◽

Discovery Studio ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Pharmacophore Models

Background: Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. Methods: DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software. Results and Conclusion: Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.

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Discovery of New Phosphoinositide 3-kinase Delta (PI3Kδ) Inhibitors via Virtual Screening using Crystallography-derived Pharmacophore Modelling and QSAR Analysis

Medicinal Chemistry ◽

10.2174/1573406415666190222125333 ◽

2019 ◽

Vol 15 (6) ◽

pp. 588-601 ◽

Cited By ~ 1

Author(s):

Mahmoud A. Al-Sha'er ◽

Rua'a A. Al-Aqtash ◽

Mutasem O. Taha

Keyword(s):

Virtual Screening ◽

Inflammatory Diseases ◽

Qsar Model ◽

Qsar Analysis ◽

Pharmacophore Modelling ◽

Physicochemical Descriptors ◽

Qsar Modelling ◽

Ic50 Values ◽

Phosphoinositide 3 Kinase ◽

Pharmacophore Models

Background: PI3Kδ is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3Kδ inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3Kδ binding. Methods: Seventeen PI3Kδ crystallographic complexes were used to extract 94 pharmacophore models. QSAR modelling was subsequently used to select the superior pharmacophore(s) that best explain bioactivity variation within a list of 79 diverse inhibitors (i.e., upon combination with other physicochemical descriptors). Results: The best QSAR model (r2 = 0.71, r2 LOO = 0.70, r2 press against external testing list of 15 compounds = 0.80) included a single crystallographic pharmacophore of optimal explanatory qualities. The resulting pharmacophore and QSAR model were used to screen the National Cancer Institute (NCI) database for new PI3Kδ inhibitors. Two hits showed low micromolar IC50 values. Conclusion: Crystallography-based pharmacophores were successfully combined with QSAR analysis for the identification of novel PI3Kδ inhibitors.

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Interaction between chromium GTP and tubulin. Stereochemistry of GTP binding, GTP hydrolysis, and microtubule stabilization

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)98905-2 ◽

1991 ◽

Vol 266 (19) ◽

pp. 12361-12368

Author(s):

M.F. Carlier ◽

D. Didry ◽

C. Valentin-Ranc

Keyword(s):

Gtp Hydrolysis ◽

Microtubule Stabilization ◽

Gtp Binding

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