Search results for "structure-activity relationship"
showing 10 items of 743 documents
QSAR of Natural Sesquiterpene Lactones as Inhibitors of Myb-dependent Gene Expression
2017
Background Protein c-Myb is a therapeutic target. Some sesquiterpene lactones suppress Myb-dependent gene expression, which results in their potential anti-cancer activity. Material & methods Database ChEMBL is a representative of lactones for physicochemical and physiochemical properties. Data presented for 31 natural lactones are discussed in terms of quantitative structureactivity relationships with the objective to predict inhibitors of Myb-induced gene expression. Several constitutional descriptors are related to structure-activity. α-Methylene-γ-lactone groups enhance while OH functions worsen potency. The latter feature is in agreement with the fact that the more lipophilic the lacto…
Pharmacophore Models Derived from Molecular Dynamics Simulations of Protein-Ligand Complexes: A Case Study
2018
A single, merged pharmacophore hypothesis is derived combining 2000 pharmacophore models obtained during a 20 ns molecular dynamics simulation of a protein-ligand complex with one pharmacophore model derived from the initial PDB structure. This merged pharmacophore model contains all features that are present during the simulation and statistical information about the dynamics of the pharmacophore features. Based on the dynamics of the pharmacophore features we derive two distinctive feature patterns resulting in two different pharmacophore models for the analyzed system – the first model consists of features that are obtained from the PDB structure and the second uses two features that ca…
Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemi…
2016
Abstract Background Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF–CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. Material and methods Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptak…
Alzheimer: A Decade of Drug Design. Why Molecular Topology can be an Extra Edge?
2017
Background The last decade was characterized by a growing awareness about the severity of dementia in the field of age-related and no age-related diseases and about the importance to invest resources in the research of new, effective treatments. Among the dementias, Alzheimer's plays a substantial role because of its extremely high incidence and fatality. Several pharmacological strategies have been tried but still now, Alzheimer keeps being an untreatable disease. In literature, the number of QSAR related drug design attempts about new treatments for Alzheimer is huge, but only few results can be considered noteworthy. Providing a detailed analysis of the actual situation and reporting the…
Synthesis, Structural Elucidation, and Biological Evaluation of NSC12, an Orally Available Fibroblast Growth Factor (FGF) Ligand Trap for the Treatme…
2016
NSC12 is an orally available pan-FGF trap able to inhibit FGF2/FGFR interaction and endowed with promising antitumor activity. It was identified by virtual screening from a NCI small molecule library, but no data were available about its synthesis, stereochemistry, and physicochemical properties. We report here a synthetic route that allowed us to characterize and unambiguously identify the structure of the active compound by a combination of NMR spectroscopy and in silico conformational analysis. The synthetic protocol allowed us to sustain experiments aimed at assessing its therapeutic potential for the treatment of FGF-dependent lung cancers. A crucial step in the synthesis generated a c…
Targeting Cavity-Creating p53 Cancer Mutations with Small-Molecule Stabilizers: the Y220X Paradigm
2020
We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of the p53 mutome, we have now analyzed the effects of other cancer-associated mutations at codon 220 on the structure, stability, and dynamics of the p53 DNA-binding domain (DBD). We found that the oncogenic Y220H, Y220N, and Y220S mutations are also highly destabilizing, suggesting that they are largely unfolded under physiological conditions. A high-resolution crystal structure of the Y220S mutant DBD revealed a mutation-induced surface crevice similar to that of Y220C, whereas the corresponding pock…
Structural photoactivation of a full-length bacterial phytochrome
2016
Time-resolved x-ray solution scattering reveals the conformational signaling mechanism of a bacterial phytochrome.
State of the Art Review and Report of New Tool for Drug Discovery
2017
BACKGROUND There are a great number of tools that can be used in QSAR/QSPR studies; they are implemented in several programs that are reviewed in this report. The usefulness of new tools can be proved through comparison, with previously published approaches. In order to perform the comparison, the most usual is the use of several benchmark datasets such as DRAGON and Sutherland's datasets. METHODS Here, an exploratory study of Atomic Weighted Vectors (AWVs), a new tool useful for drug discovery using different datasets, is presented. In order to evaluate the performance of the new tool, several statistics and QSAR/QSPR experiments are performed. Variability analyses are used to quantify the…
A peptide from human β thymosin as a platform for the development of new anti-biofilm agents for Staphylococcus spp. and Pseudomonas aeruginosa
2016
Conventional antibiotics might fail in the treatment of biofilm-associated infections causing infection recurrence and chronicity. The search for antimicrobial peptides has been performed with the aim to discover novel anti-infective agents active on pathogens in both planktonic and biofilm associated forms. The fragment 9-19 of human thymosin β4 was studied through 1 μs MD simulation. Two main conformations of the peptide were detected, both constituted by a central hydrophobic core and by the presence of peripheral charged residues suggesting a possible mechanism of interaction with two models of biological membranes, related to eukaryotic or bacterial membrane respectively. In addition, …
What place does molecular topology have in today’s drug discovery?
2020
Introduction: Most methods in molecular and drug design are currently based on physicochemical descriptors. However, molecular topology, which relies on topological descriptors, has also shown value for molecular design even if it does not take into account the physical or chemical properties of ligands and receptors, including the ligand-receptor interaction itself. Areas covered: Herein, the authors provide new insights into the importance of molecular topology according to some of the latest discoveries in physics and chemistry. Furthermore, the authors report on the most significant achievements in drug design using molecular topology over the last 5 years and give their expert perspect…