A new method for the postprocessing of docking outputs has been developed, based on encoding putative 3D binding modes (docking solutions) as ligand-protein interactions into simple bit strings, a method analogous to the structural interaction fingerprint. Instead of employing traditional scoring functions, the method uses a series of new, knowledge-based scores derived from the similarity of the bit strings for each docking solution to that of a known reference binding mode. A GOLD docking study was carried out using the Bissantz estrogen receptor antagonist set along with the new scoring method. Superior recovery rates, with up to 2-fold enrichments, were observed when the new knowledge-based scoring was compared to the GOLD fitness score. In addition, top ranking sets of molecules (actives and potential actives or decoys) were structurally diverse with low molecular weights and structural complexities. Principal component analysis and clustering of the fingerprints permits the easy separation of active from inactive binding modes and the visualization of diverse binding modes.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/ci050420d | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study.
J Chem Inf Model
January 2025
Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 00 Brno, Czech Republic.
RNA recognition motifs (RRMs) are a key class of proteins that primarily bind single-stranded RNAs. In this study, we applied standard atomistic molecular dynamics simulations to obtain insights into the intricate binding dynamics between uridine-rich RNAs and TbRGG2 RRM using the recently developed OL3-Stafix AMBER force field, which improves the description of single-stranded RNA molecules. Complementing structural experiments that unveil a primary binding mode with a single uridine bound, our simulations uncover two supplementary binding modes in which adjacent nucleotides encroach upon the binding pocket.
View Article and Find Full Text PDFFlipped binding modes for the same agonist in closely related neuropeptide-gated ion channels.
Biophys J
January 2025
Michael Sars Centre, University of Bergen, Norway. Electronic address:
Neuropeptides are inter-cellular signaling molecules occurring throughout animals. Most neuropeptides bind and activate G-protein coupled receptors, but some also activate ionotropic receptors (or "ligand-gated ion channels"). This is exemplified by the tetra-peptide H-Phe-Met-Arg-Phe-NH (FMRFa), which activates mollusc and annelid FMRFa-gated sodium channels (FaNaCs) from the trimeric degenerin/epithelial sodium channel superfamily.
View Article and Find Full Text PDFInvestigation of Thiazolidine-2,4-Dione Derivatives as Acetylcholinesterase Inhibitors: Synthesis, In Vitro Biological Activities and In Silico Studies.
ChemistryOpen
January 2025
Department of Chemistry, Faculty of Sciences, University of Guilan, Rasht, 4193833697, Iran.
The inhibition of acetylcholinesterase (AChE), an enzyme responsible for the inactivation and decrease in acetylcholine in the cholinergic pathway, has been considered an attractive target for small-molecule drug discovery in Alzheimer's disease (AD) therapy. In the present study, a series of TZD derivatives were designed, synthesized, and studied for drug likeness, blood-brain barrier (BBB) permeability, and adsorption, distribution, metabolism, excretion, and toxicity (ADMET). Additionally, docking studies of the designed compounds were performed on AChE.
View Article and Find Full Text PDFExploring the Binding Mechanism of ADGRG2 Through Metadynamics and Biochemical Analysis.
Int J Mol Sci
December 2024
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
G protein-coupled receptors (GPCRs) play essential roles in numerous physiological processes and are key targets for drug development. Among them, adhesion GPCRs (aGPCRs) stand out for their unique domain structures and diverse functions. ADGRG2 is a member of the aGPCR family and is involved in the regulation of various systems in the human body, including reproductive, nervous, cardiovascular, and endocrine systems.
View Article and Find Full Text PDFThe Diverse Binding Modes Explain the Nanomolar Levels of Inhibitory Activities Against 1-Deoxy-d-Xylulose 5-Phosphate Reductoisomerase from Exhibited by Reverse Hydroxamate Analogs of Fosmidomycin with Varying -Substituents.
Molecules
December 2024
School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan.
It is established that reverse hydroxamate analogs of fosmidomycin inhibit the growth of by inhibiting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate pathway, which is absent in humans. Recent biochemical studies have demonstrated that novel reverse fosmidomycin analogs with phenylalkyl substituents at the hydroxamate nitrogen exhibit inhibitory activities against DXR at the nanomolar level. Moreover, crystallographic analyses have revealed that the phenyl moiety of the -phenylpropyl substituent is accommodated in a previously unidentified subpocket within the active site of DXR.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!