☆ 4.4 Article

Dynamics and structural determinants of ligand recognition of the 5-HT6 receptor

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN (2015)

Get Full Text
Add to Collection

Journal

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 29, Issue 12, Pages 1137-1149

Publisher

SPRINGER
DOI: 10.1007/s10822-015-9883-y

Keywords

5-HT6 receptor; Molecular dynamics; Docking; Enrichment; Virtual screening

Categories

Biochemistry & Molecular Biology Biophysics Computer Science, Interdisciplinary Applications

Funding

  1. National Brain Research Program [KTIA-NAP-13-1-2013-0001]
  2. Marie Curie Intra European Fellowship within 7th European Community Framework Programme

Ask authors/readers for more resources

Protocol

Community support

Reagent

Community support

In order to identify molecular models of the human 5-HT6 receptor suitable for virtual screening, homology modeling and membrane-embedded molecular dynamics simulations were performed. Structural requirements for robust enrichment were assessed by an unbiased chemometric analysis of enrichments from retrospective virtual screening studies. The two main structural features affecting enrichment are the outward movement of the second extracellular loop and the formation of a hydrophobic cavity deep in the binding site. These features appear transiently in the trajectories and furthermore the stretches of uniformly high enrichment may only last 4-10 ps. The formation of the inner hydrophobic cavity was also linked to the active-like to inactive-like transition of the receptor, especially the so-called connector region. The best structural models provided significant and robust enrichment over three independent ligand sets.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.4
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

Review Chemistry, Physical

The role of quantum chemistry in covalent inhibitor design

Levente M. Mihalovits, Gyorgy G. Ferenczy, Gyorgy M. Keseru

Summary: The recent rise of targeted covalent inhibitors in drug discovery presents new opportunities and challenges for quantum chemical reactivity calculations. These calculations are crucial in determining inhibitory potency by predicting intrinsic reactivities of covalent ligands. Mixed quantum mechanical/molecular mechanical potentials provide a comprehensive description of covalent ligand binding mechanisms, while efficient QM/MM predictions of ligand reactivities are highly useful in covalent drug discovery.

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY (2022)

Add to Collection
Article Chemistry, Medicinal

Consensus Virtual Screening Identified [1,2,4]Triazolo[1,5-b]isoquinolines As MELK Inhibitor Chemotypes

Anita Racz, Roberta Palko, Dorottya Csanyi, Zsuzsanna Riedl, David Bajusz, Gyorgy M. Keseru

Summary: This study discovered a series of new MELK inhibitors through virtual screening, and disclosed the synthesis and bioactivity of this class of compounds for the first time, providing a new direction for anti-cancer drug development.

CHEMMEDCHEM (2022)

Add to Collection
Review Pharmacology & Pharmacy

Electrophilic warheads in covalent drug discovery: an overview

Nikolett Peczka, Zoltan Orgovan, Peter Abranyi-Balogh, Gyorgy Miklos Keseru

Summary: This review provides an overview of electrophilic warheads used for protein labeling in chemical biology and medicinal chemistry. The warheads are discussed based on targeted residues, mechanism, and selectivity, and analyzed using multiple datasets. Despite the availability of numerous electrophilic warheads, only a fraction of them are used in current drug discovery projects. Recent studies have identified new tractable residues, but the discovery of new warheads for these residues is still needed.

EXPERT OPINION ON DRUG DISCOVERY (2022)

Add to Collection
Article Pharmacology & Pharmacy

Effects of sub-chronic, in vivo administration of sigma non-opioid intracellular receptor 1 ligands on platelet and aortic arachidonate cascade in rats

Sandor Vaczi, Lilla Barna, Krisztian Laczi, Ferenc Tomosi, Gabor Rakhely, Botond Penke, Livia Fulop, Ferenc Bogar, Tamas Janaky, Maria A. Deli, Zsofia Mezei

Summary: This study examined the effects of sigma-1 receptor ligands on platelet and vascular eicosanoid synthesis. The results showed that these ligands can modify the synthesis of eicosanoids in platelets and vessels and play a role in multiple steps of arachidonic acid metabolism.

EUROPEAN JOURNAL OF PHARMACOLOGY (2022)

Add to Collection
Review Biochemistry & Molecular Biology

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

Ferenc Bogar, Livia Fulop, Botond Penke

Summary: Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of cells and their networks in the nervous system. Currently, there are no treatments available to stop the progression of NDDs. Neuroinflammation has been a focus in drug development for NDDs. The Sigma-1 receptor (Sig-1R) is a potential target for NDD drug development, as its activation can provide neuroprotection and slow down the progression of NDDs.

BIOMOLECULES (2022)

Add to Collection
Review Pharmacology & Pharmacy

Maximizing the integration of virtual and experimental screening in hit discovery

David Bajusz, Gyorgy M. Keseru

Summary: Experimental and virtual screening are complementary approaches that should be integrated in lead discovery settings. Virtual screening can access extremely large synthetically feasible chemical space that can be effectively searched on GPU clusters or cloud architectures. Experimental screening provides reliable datasets by quantitative HTS applications, and DNA-encoded libraries (DEL) have enlarged the chemical space covered by these technologies. These developments, together with the use of artificial intelligence methods, represent new options for their efficient integration. The case studies discussed here demonstrate the benefits of complementary strategies, such as focused and iterative screening.

EXPERT OPINION ON DRUG DISCOVERY (2022)

Add to Collection
Article Chemistry, Medicinal

Conservation of Allosteric Ligand Binding Sites in G-Protein Coupled Receptors

Amanda E. Wakefield, David Bajusz, Dima Kozakov, Gyoergy M. Keseru, Sandor Vajda

Summary: Despite the limited number of GPCR structures cocrystallized with allosteric inhibitors, protein mapping has revealed the presence of druggable sites at the same locations in a large variety of GPCRs. These sites cluster at nine distinct locations and can be specifically targeted for allosteric modulation across GPCRs. The FTMap server facilitates protein mapping and is freely available for academic and governmental use.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2022)

Add to Collection
Article Chemistry, Medicinal

Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors

Peter Abranyi-Balogh, Aaron Keeley, Gyorgy G. Ferenczy, Laszlo Petri, Timea Imre, Katarina Grabrijan, Martina Hrast, Damijan Knez, Janez Ilas, Stanislav Gobec, Gyorgy M. Keseru

Summary: The second generation of heterocyclic electrophiles, the quaternized analogue of the heterocyclic covalent fragment library, showed improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH reactivity assay, and thrombin counter screen were used to explain the improved reactivity and selectivity of the N-methylated heterocycles and compare the two generations of heterocyclic electrophiles.

PHARMACEUTICALS (2022)

Add to Collection
Review Biochemistry & Molecular Biology

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer's Disease

Botond Penke, Maria Szucs, Ferenc Bogar

Summary: Alzheimer's disease is an incurable neurodegenerative disorder that is mostly caused by aging, genetic factors, and epigenetic changes. Beta-amyloid and hyperphosphorylated tau proteins play a crucial role in the development of this disease. Inhibiting the formation of toxic aggregates of these proteins has been a major target for drug research, and recent success in A beta clearance has provided new possibilities for AD treatment.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

Add to Collection
Article Biochemistry & Molecular Biology

Activation-Free Sulfonyl Fluoride Probes for Fragment Screening

Laszlo Petri, Peter Aabranyi-Balogh, Noemi Csorba, Aaron Keeley, Jozsef Simon, Ivan Randelovic, Jozsef Tovari, Gitta Schlosser, Daniel Szabo, Laszlo Drahos, Gyoergy M. Keseru

Summary: SuFEx chemistry is based on the unique reactivity of the sulfonyl fluoride group with a range of nucleophiles. Sulfonyl fluorides can label multiple nucleophilic amino acid residues, making them popular in both chemical biology and medicinal chemistry applications. In this study, a small sulfonyl fluoride library was synthesized and characterized, resulting in the identification of a 3-carboxybenzenesulfonyl fluoride warhead for tagging nucleophilic residues. Coupling diverse fragments to this warhead could yield a library of sulfonyl fluoride bits (SuFBits) for screening against protein targets, facilitated by mass spectrometry identification of weak fragments.

MOLECULES (2023)

Add to Collection
Article Biochemistry & Molecular Biology

SH2db, an information system for the SH2 domain

David Bajusz, Gaspar Pandy-Szekeres, Agnes Takacs, Elvin D. de Araujo, Gyorgy M. Keseru

Summary: SH2db is a comprehensive structural database and webserver for SH2 domain structures, providing search, browse, and download functions. It assists researchers in their day-to-day work and serves as a valuable resource for SH2 domain-related research.

NUCLEIC ACIDS RESEARCH (2023)

Add to Collection
Article Pharmacology & Pharmacy

Structural Adaptation of the Single-Stranded DNA-Binding Protein C-Terminal to DNA Metabolizing Partners Guides Inhibitor Design

Attila Tokoli, Brigitta Bodnar, Ferenc Bogar, Gabor Paragi, Anasztazia Hetenyi, Eva Bartus, Edit Weber, Zsofia Hegedus, Zoltan Szabo, Gabor Kecskemeti, Gerda Szakonyi, Tamas A. Martinek

Summary: Single-stranded DNA-binding protein (SSB) plays a crucial role in bacterial interactions and is a potential target for antimicrobial therapy. This study focuses on understanding the structural adaptation of the disordered SSB C-terminus (SSB-Ct) to DNA metabolizing enzymes and designing high-affinity SSB mimetic inhibitors. Molecular dynamics simulations and experimental data reveal the transient interactions and increased affinity of SSB-Ct with the hot spots on ExoI and RecO. These findings suggest the potential of SSB-Ct mimetics in binding to DNA metabolizing targets.

PHARMACEUTICS (2023)

Add to Collection
Article Chemistry, Physical

Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones

Levente M. Mihalovits, Levente Kollar, David Bajusz, Damijan Knez, Kristof Bozovicar, Timea Imre, Gyorgy G. Ferenczy, Stanislav Gobec, Gyorgy M. Keseru

Summary: This study investigates the mechanism of covalent labeling of cysteines using heterocyclic thiones as reversible covalent warheads. The main protease of SARS-CoV-2 harboring Cys145 was chosen as the target, and molecular dynamics simulations and experimental validations were conducted.

CHEMPHYSCHEM (2023)

Add to Collection
Review Pharmacology & Pharmacy

Covalent fragment approaches targeting non-cysteine residues

Noemi Csorba, Peter Abranyi-Balogh, Gyorgy M. Keseru

Summary: Covalent fragment approaches combine the advantages of covalent binders and fragment-based drug discovery (FBDD) for target identification and validation. Recent studies have expanded the chemistries of different warheads to target protein nucleophiles other than cysteine residues. This review discusses these newly developed amino-acid-specific and promiscuous warheads, as well as emerging labeling chemistries. The applications of covalent fragments in the development of molecular glues and proteolysis-targeting chimeras (PROTACs) are highlighted, along with their utility in chemical proteomics-based target identification and validation.

TRENDS IN PHARMACOLOGICAL SCIENCES (2023)

Add to Collection
Article Chemistry, Organic

A stepwise one-pot synthesis of aliphatic thiols and their derivatives from acrylamides and sulfur

Andras Gy. Nemeth, Renata Szabo, Krisztina Nemeth, Gyorgy M. Keseru, Peter Abranyi-Balogh

Summary: This study discovered the reactivity of easily accessible electron deficient alkenes towards sulfur and developed a new pseudo-multicomponent reaction for the preparation of polysulfides.

ORGANIC & BIOMOLECULAR CHEMISTRY (2022)

Add to Collection
No Data Available
Webinars Posters Questions Hubs Funding Journals Papers Connect Collections Reviewers About Us FAQs Mobile App Privacy Policy Terms of Use
© Peeref 2019-2024. All rights reserved.