Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds.

08:00 EDT 9th April 2019 | BioPortfolio

Summary of "Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds."

Transcriptional repressor EthR from Mycobacterium tuberculosis is a valuable target for antibiotic booster drugs. We previously reported a virtual screening campaign to identify EthR inhibitors for development. Two ligand binding orientations were often proposed, though only the top scoring pose was utilised for filtering of the large dataset. We obtained biophysically validated hits, some which yielded complex crystal structures. In some cases, the crystallised binding mode and top scoring mode agree, while for others the alternate ligand binding orientation was found. In this contribution we combine rigid docking, MD simulations and the LIE method to calculate free energies of binding and derive relative binding energies for a number of EthR inhibitors in both modes. This strategy allowed us to correctly predict the most favourable orientation. Therefore, this widely applicable approach will be suitable to triage multiple binding modes within EthR and other potential drug targets with similar characteristics.


Journal Details

This article was published in the following journal.

Name: The journal of physical chemistry letters
ISSN: 1948-7185


DeepDyve research library

PubMed Articles [14832 Associated PubMed Articles listed on BioPortfolio]

Simple Entropy Terms for End-Point Binding Free Energy Calculations.

We introduce a number of computationally inexpensive modifications to the MM/PBSA and MM/GBSA estimators for binding free energies, which are based on average receptor-ligand interaction energies in s...

Substrate and inhibitor binding to the serotonin transporter: insights from computational, crystallographic, and functional studies.

The serotonin transporter (SERT) belongs to the monoamine transporter family, which also includes the dopamine and norepinephrine transporters. SERT is essential for regulating serotonergic signaling ...

Suitability of MMGBSA for the Selection of Correct Ligand Binding Modes from Docking Results.

The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct bindin...

Binding of Pb-Melatonin and Pb-(Melatonin-metabolites) complexes with DMT1 and ZIP8: implications for lead detoxification.

We have applied the docking methodology to characterize the binding modes of the divalent metal transporter 1 (DMT1) and the zinc transporter 8 (ZIP8) protein channels with: melatonin, some melatonin ...

Predicting the Binding of Fatty Acid Amide Hydrolase Inhibitors by Free Energy Perturbation (FEP).

Since a goal of most drug discovery projects in either academia or industry is to design molecules that selectively bind to the desired protein, determination of protein-ligand binding free energies i...

Clinical Trials [4014 Associated Clinical Trials listed on BioPortfolio]

First-in-Human Positron Emission Tomography Study Using the 18F-αvβ6-Binding-Peptide

This clinical trial studies the side effects of 18F-alphavbeta6-binding-peptide and how well it works in imaging patients with primary or cancer that has spread to the breast, colorectal, ...

Study of the Role of Soluble Inhibitor of Interleukin 22, Interleukin 22 Binding Protein (IL-22BP), in Chronic Inflammatory Bowel Disease

IL-22 is an IL-10 family cytokine that plays major actions to increase intestinal epithelial barrier function and regeneration during experimental colitis. IL-22 binding protein is a small...

Heparin Binding Protein in Early Sepsis Diagnosis

The primary objective of this study is to use heparin-binding protein (HBP) concentration to indicate the presence, or outcome, of sepsis over 72 hours after ED admission. The secondary ob...

Evaluation of the Heparin Binding Protein Levels in Sepsis

Present criteria used to define sepsis are non-specific, making it difficult to both distinguish sepsis from other diseases and to predict which patients are likely to become more severely...

Identification of Donors of CD36-Deficient Platelets Among Japanese Individuals on the NIH Campus

Plasma histidine-rich glycoprotein (HRG) binds to platelets in the presence of zinc (1). This binding is totally blocked by a monoclonal antibody directed against platelet membrane CD36. ...

Medical and Biotech [MESH] Definitions

GTP-BINDING PROTEINS that contain three non-identical subunits. They are found associated with members of the seven transmembrane domain superfamily of G-PROTEIN-COUPLED RECEPTORS. Upon activation the GTP-BINDING PROTEIN ALPHA SUBUNIT of the complex dissociates leaving a dimer of a GTP-BINDING PROTEIN BETA SUBUNIT bound to a GTP-BINDING PROTEIN GAMMA SUBUNIT.

A transcription factor that possesses DNA-binding and E2F-binding domains but lacks a transcriptional activation domain. It is a binding partner for E2F TRANSCRIPTION FACTORS and enhances the DNA binding and transactivation function of the DP-E2F complex.

A member of the p300-CBP transcription factor family that was initially identified as a binding partner for CAMP RESPONSE ELEMENT-BINDING PROTEIN. Mutations in CREB-binding protein are associated with RUBINSTEIN-TAYBI SYNDROME.

The major sequence-specific DNA-binding component involved in the activation of transcription of RNA POLYMERASE II. It was originally described as a complex of TATA-BOX BINDING PROTEIN and TATA-BINDING PROTEIN ASSOCIATED FACTORS. It is now know that TATA BOX BINDING PROTEIN-LIKE PROTEINS may take the place of TATA-box binding protein in the complex.

A poly(A) binding protein that has a variety of functions such as mRNA stabilization and protection of RNA from nuclease activity. Although poly(A) binding protein I is considered a major cytoplasmic RNA-binding protein it is also found in the CELL NUCLEUS and may be involved in transport of mRNP particles.

Quick Search


DeepDyve research library

Relevant Topics

Antiretroviral Therapy Clostridium Difficile Ebola HIV & AIDS Infectious Diseases Influenza Malaria Measles Sepsis Swine Flu Tropical Medicine Tuberculosis Infectious diseases are caused by pathogenic...

Drug Discovery
Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...

Searches Linking to this Article