Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Impact of the Recent Mouse P-Glycoprotein Structure for Structure-Based Ligand Design.

ABSTRACT: P-Glycoprotein (P-gp), a transmembrane, ATP-dependent drug efflux transporter, has attracted considerable interest both with respect to its role in tumour cell multidrug resistance and in absorption-distribution and elimination of drugs. Although known since more than 30 years, the understanding of the molecular basis of drug/transporter interaction is still limited, which is mainly due to the lack of structural information available. However, within the past decade X-ray structures of several bacterial homologues as well as very recently also of mouse P-gp have become available. Within this review we give an overview on the current status of structural information available and on its impact for structure-based drug design.

SUBMITTER: Klepsch F

PROVIDER: S-EPMC6422301 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Impact of the Recent Mouse P-Glycoprotein Structure for Structure-Based Ligand Design.

Klepsch Freya F Ecker Gerhard F GF

Molecular informatics 20100420 4

P-Glycoprotein (P-gp), a transmembrane, ATP-dependent drug efflux transporter, has attracted considerable interest both with respect to its role in tumour cell multidrug resistance and in absorption-distribution and elimination of drugs. Although known since more than 30 years, the understanding of the molecular basis of drug/transporter interaction is still limited, which is mainly due to the lack of structural information available. However, within the past decade X-ray structures of several b ...[more]

PMID: 27463054

Similar Datasets

Recent Trends and Applications of Molecular Modeling in GPCR⁻Ligand Recognition and Structure-Based Drug Design.

Project description:G protein-coupled receptors represent the largest family of human membrane proteins and are modulated by a variety of drugs and endogenous ligands. Molecular modeling techniques, especially enhanced sampling methods, have provided significant insight into the mechanism of GPCR⁻ligand recognition. Notably, the crucial role of the membrane in the ligand-receptor association process has earned much attention. Additionally, docking, together with more accurate free energy calculation methods, is playing an important role in the design of novel compounds targeting GPCRs. Here, we summarize the recent progress in the computational studies focusing on the above issues. In the future, with continuous improvement in both computational hardware and algorithms, molecular modeling would serve as an indispensable tool in a wider scope of the research concerning GPCR⁻ligand recognition as well as drug design targeting GPCRs.

| S-EPMC6073596 | biostudies-literature

Structure-Based Design of Prefusion-Stabilized Filovirus Glycoprotein Trimers.

Project description:Ebola virus causes severe hemorrhagic fever, often leading to death in humans. The trimeric fusion glycoprotein (GP) is the sole target for neutralizing antibodies and is the major focus of vaccine development. Soluble GP ectodomains are unstable and mostly monomeric when not fused to a heterologous trimerization domain. Here, we report structure-based designs of Ebola and Marburg GP trimers based on a stabilizing mutation in the hinge loop in refolding region 1 and substitution of a partially buried charge at the interface of the GP1 and GP2 subunits. The combined substitutions (T577P and K588F) substantially increased trimer expression for Ebola GP proteins. We determined the crystal structure of stabilized GP from the Makona Zaire ebolavirus strain without a trimerization domain or complexed ligand. The structure reveals that the stabilized GP adopts the same trimeric prefusion conformation, provides insight into triggering of GP conformational changes, and should inform future filovirus vaccine development.

| S-EPMC7118701 | biostudies-literature

Recent progress in structure-based anti-influenza drug design.

Project description:Seasonal and pandemic influenza have caused high morbidity and mortality worldwide. Recent emergence of influenza A H5N1 and H1N1 strains has heightened concern, especially as a result of their drug resistance. The life cycle of influenza viruses has been well studied and nearly all the viral proteins are becoming potential therapeutic targets. In this review, we present an overview of recent progress in structure-based anti-influenza drug design, paying close attention to the increasing role of computation and strategies for overcoming drug resistance.

| S-EPMC3459301 | biostudies-literature

Ligand and structure-based classification models for prediction of P-glycoprotein inhibitors.

Project description:The ABC transporter P-glycoprotein (P-gp) actively transports a wide range of drugs and toxins out of cells, and is therefore related to multidrug resistance and the ADME profile of therapeutics. Thus, development of predictive in silico models for the identification of P-gp inhibitors is of great interest in the field of drug discovery and development. So far in silico P-gp inhibitor prediction was dominated by ligand-based approaches because of the lack of high-quality structural information about P-gp. The present study aims at comparing the P-gp inhibitor/noninhibitor classification performance obtained by docking into a homology model of P-gp, to supervised machine learning methods, such as Kappa nearest neighbor, support vector machine (SVM), random fores,t and binary QSAR, by using a large, structurally diverse data set. In addition, the applicability domain of the models was assessed using an algorithm based on Euclidean distance. Results show that random forest and SVM performed best for classification of P-gp inhibitors and noninhibitors, correctly predicting 73/75% of the external test set compounds. Classification based on the docking experiments using the scoring function ChemScore resulted in the correct prediction of 61% of the external test set. This demonstrates that ligand-based models currently remain the methods of choice for accurately predicting P-gp inhibitors. However, structure-based classification offers information about possible drug/protein interactions, which helps in understanding the molecular basis of ligand-transporter interaction and could therefore also support lead optimization.

| S-EPMC3904775 | biostudies-literature

Rational design of a ligand-based antagonist of jasmonate perception

Project description:The phytohormone (+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile) is a major regulator of developmental and stress responses in plants. The perception of JA-Ile involves the formation of a ternary complex with the F-box protein COI1 and a member of the JAZ family of co-repressors, which leads to JAZ degradation. Coronatine (COR) is a bacterial phytotoxin that functionally mimics JA-Ile and interacts with the co-receptor COI1-JAZ complex with higher affinity than JA-Ile. Based on the crystal structure of the co-receptor, we designed ligand derivatives that spatially impede the interaction of the co-receptor proteins and, therefore, should act as competitive antagonists of COR or JA-Ile. One derivative, Coronatine O-methyloxime (COR-MO), shows a strong activity preventing COI-JAZ interaction and the subsequent JAZ degradation. COR-MO efficiently reverts the effects of JA-Ile or COR treatments on JA-mediated responses, such as anthocyanin accumulation, root-growth inhibition and gene expression in Arabidopsis plants. Moreover, it potentiates plant resistance preventing the effect of bacterially produced COR during Pseudomonas syringae infections in different plant species. In addition to the utility of COR-MO for Plant Biology research, our results underscore its biotechnological and agronomical potential for a safer and sustainable agriculture. Two-condition experiment, Col-0 vs Col-0 plants treated 2h with Coronatine 0-methyloxime (COR-MO) and Col-0 plants treated 2h with Coronatine vs Col-0 plants treated 2h with Coronatine plus COR-MO. Biological replicates: 4 control and 4 treated replicates

2014-06-20 | E-GEOD-56027 | biostudies-arrayexpress

Structure-Based Design of Antivirals against Envelope Glycoprotein of Dengue Virus.

Project description:Dengue virus (DENV) presents a significant threat to global public health with more than 500,000 hospitalizations and 25,000 deaths annually. Currently, there is no clinically approved antiviral drug to treat DENV infection. The envelope (E) glycoprotein of DENV is a promising target for drug discovery as the E protein is important for viral attachment and fusion. Understanding the structure and function of DENV E protein has led to the exploration of structure-based drug discovery of antiviral compounds and peptides against DENV infections. This review summarizes the structural information of the DENV E protein with regards to DENV attachment and fusion. The information enables the development of antiviral agents through structure-based approaches. In addition, this review compares the potency of antivirals targeting the E protein with the antivirals targeting DENV multifunctional enzymes, repurposed drugs and clinically approved antiviral drugs. None of the current DENV antiviral candidates possess potency similar to the approved antiviral drugs which indicates that more efforts and resources must be invested before an effective DENV drug materializes.

| S-EPMC7232406 | biostudies-literature

Rational design of a ligand-based antagonist of jasmonate perception

2014-06-20 | GSE56027 | GEO

Structure-based ligand design of novel bacterial RNA polymerase inhibitors.

Project description:Bacterial RNA polymerase (RNAP) is essential for transcription and is an antibacterial target for small molecule inhibitors. The binding region of myxopyronin B (MyxB), a bacterial RNAP inhibitor, offers the possibility of new inhibitor design. The molecular design program SPROUT has been used in conjunction with the X-ray cocrystal structure of Thermus thermophilus RNAP with MyxB to design novel inhibitors based on a substituted pyridyl-benzamide scaffold. A series of molecules, with molecular masses <350 Da, have been prepared using a simple synthetic approach. A number of these compounds inhibited Escherichia coli RNAP.

| S-EPMC4017976 | biostudies-literature

Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus.

Project description:Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.

| S-EPMC4461862 | biostudies-literature

Identification of ligand templates using local structure alignment for structure-based drug design.

Project description:With a rapid increase in the number of high-resolution protein-ligand structures, the known protein-ligand structures can be used to gain insight into ligand-binding modes in a target protein. On the basis of the fact that the structurally similar binding sites share information about their ligands, we have developed a local structure alignment tool, G-LoSA (graph-based local structure alignment). The known protein-ligand binding-site structure library is searched by G-LoSA to detect binding-site structures with similar geometry and physicochemical properties to a query binding-site structure regardless of sequence continuity and protein fold. Then, the ligands in the identified complexes are used as templates (i.e., template ligands) to predict/design a ligand for the target protein. The performance of G-LoSA is validated against 76 benchmark targets from the Astex diverse set. Using the currently available protein-ligand structure library, G-LoSA is able to identify a single template ligand (from a nonhomologous protein complex) that is highly similar to the target ligand in more than half of the benchmark targets. In addition, our benchmark analyses show that an assembly of structural fragments from multiple template ligands with partial similarity to the target ligand can be used to design novel ligand structures specific to the target protein. This study clearly indicates that a template-based ligand modeling has potential for de novo ligand design and can be a complementary approach to the receptor structure based methods.

| S-EPMC3478504 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data