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1.
Arch Pharm (Weinheim) ; 356(12): e2300387, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37806764

ABSTRACT

Fingolimod, the prodrug of fingolimod-1-phosphate (F1P), was the first sphingosine-1-phosphate receptor (S1PR) modulator approved for multiple sclerosis. F1P unselectively targets all five S1PR subtypes. While agonism (functional antagonism via receptor internalization) at S1PR1 leads to the desired immune modulatory effects, agonism at S1PR3 is associated with cardiac adverse effects. This motivated the development of S1PR3 -sparing compounds and led to a second generation of S1PR1,5 -selective ligands like siponimod and ozanimod. Our method combines molecular dynamics simulations and three-dimensional pharmacophores (dynophores) and enables the elucidation of S1PR subtype-specific binding site characteristics, visualizing also subtle differences in receptor-ligand interactions. F1P and the endogenous ligand sphingosine-1-phosphate bind to the orthosteric pocket of all S1PRs, but show different binding mode dynamics, uncovering potential starting points for the development of subtype-specific ligands. Our study contributes to the mechanistic understanding of the selectivity profile of approved drugs like ozanimod and siponimod and pharmaceutical tool compounds like CYM5541.


Subject(s)
Fingolimod Hydrochloride , Receptors, Lysosphingolipid , Sphingosine-1-Phosphate Receptors , Receptors, Lysosphingolipid/metabolism , Ligands , Structure-Activity Relationship
2.
Pharmaceuticals (Basel) ; 15(11)2022 Oct 22.
Article in English | MEDLINE | ID: mdl-36355476

ABSTRACT

G protein-coupled receptors (GPCRs) are amongst the most pharmaceutically relevant and well-studied protein targets, yet unanswered questions in the field leave significant gaps in our understanding of their nuanced structure and function. Three-dimensional pharmacophore models are powerful computational tools in in silico drug discovery, presenting myriad opportunities for the integration of GPCR structural biology and cheminformatics. This review highlights success stories in the application of 3D pharmacophore modeling to de novo drug design, the discovery of biased and allosteric ligands, scaffold hopping, QSAR analysis, hit-to-lead optimization, GPCR de-orphanization, mechanistic understanding of GPCR pharmacology and the elucidation of ligand-receptor interactions. Furthermore, advances in the incorporation of dynamics and machine learning are highlighted. The review will analyze challenges in the field of GPCR drug discovery, detailing how 3D pharmacophore modeling can be used to address them. Finally, we will present opportunities afforded by 3D pharmacophore modeling in the advancement of our understanding and targeting of GPCRs.

3.
Mol Inform ; 40(9): e2100031, 2021 09.
Article in English | MEDLINE | ID: mdl-34378348

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to be a global threat, causing millions of deaths worldwide. SARS-CoV-2 is an enveloped virus with spike (S) glycoproteins conferring binding to the host cell's angiotensin-converting enzyme 2 (ACE2), which is critical for cellular entry. The host range of the virus extends well beyond humans and non-human primates. Natural and experimental infections have confirmed the high susceptibility of cats, ferrets, and Syrian hamsters, whereas dogs, mice, rats, pigs, and chickens are refractory to SARS-CoV-2 infection. To investigate the underlying reason for the variable susceptibility observed in different species, we have developed molecular descriptors to efficiently analyse dynamic simulation models of complexes between SARS-CoV-2 S and ACE2. Our extensive analyses represent the first systematic structure-based approach that allows predictions of species susceptibility to SARS-CoV-2 infection.


Subject(s)
SARS-CoV-2/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , Cats , Dogs , Ferrets , Haplorhini , Humans , Mesocricetus , Mice , Molecular Dynamics Simulation , Rats , SARS-CoV-2/metabolism , Species Specificity , Swine
4.
Molecules ; 26(2)2021 Jan 10.
Article in English | MEDLINE | ID: mdl-33435264

ABSTRACT

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Diabetes Mellitus/drug therapy , Enzyme Inhibitors , Hypoglycemic Agents , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Aldehyde Reductase/metabolism , Animals , Diabetes Mellitus/enzymology , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Hep G2 Cells , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Ligands , Mice , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Structure-Activity Relationship
6.
Int J Mol Sci ; 21(24)2020 Dec 20.
Article in English | MEDLINE | ID: mdl-33419260

ABSTRACT

G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known ß-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors.


Subject(s)
Ergotamine/chemistry , Lysergic Acid Diethylamide/chemistry , Protein Conformation , Receptor, Serotonin, 5-HT2B/chemistry , Binding Sites/genetics , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Receptor, Serotonin, 5-HT2B/genetics , Receptor, Serotonin, 5-HT2B/ultrastructure , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/ultrastructure , Serotonin/chemistry , Signal Transduction/genetics , beta-Arrestins/chemistry , beta-Arrestins/genetics , beta-Arrestins/ultrastructure
7.
Drug Discov Today ; 24(4): 1031-1037, 2019 04.
Article in English | MEDLINE | ID: mdl-30831262

ABSTRACT

G-protein-coupled receptors (GPCRs) represent important drug targets with complex pharmacological characteristics. Biased signaling represents one important dimension, describing ligand-dependent shifts of naturally imprinted signaling profiles. Because biased GPCR modulators provide potential therapeutic benefits including higher efficiencies and reduced adverse effects, the identification of such ligands as drug candidates is highly desirable. This review aims to provide an overview of the challenges and strategies in the discovery of biased ligands. We show different approaches for biased ligand discovery in the example of G-protein-biased opioid analgesics and discuss possibilities to design biased ligands by targeting extracellular receptor regions.


Subject(s)
Drug Discovery , Receptors, G-Protein-Coupled/metabolism , Analgesics, Opioid/pharmacology , Animals , Humans , Ligands , Signal Transduction
8.
Asian Cardiovasc Thorac Ann ; 26(3): 207-211, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29411632

ABSTRACT

Background Thymoma is a primary tumor derived from the epithelial cells of the thymus, which is commonly seen in the mediastinum. Surgical thymectomy is the radical treatment for thymoma. The recent introduction of video-assisted thoracoscopic surgery has improved the quality of thymectomy surgery. The clinical characteristics of thymoma and the outcomes of video-assisted thoracoscopic thymectomy in Vietnamese patients are still lacking. The objectives of this study were to investigate the clinical and laboratory characteristics of thymoma and to evaluate the early results of video-assisted thoracoscopic thymectomy for thymoma in Vietnamese patients. Methods All 53 thymoma patients with or without myasthenia gravis who underwent video-assisted thoracoscopic thymectomy in Military Hospital 103, Vietnam, from October 2013 to July 2017 were included. Results The mean age was 46.5 7.1 years, and the female/male ratio was 1.2:1. Myasthenia gravis, mostly stage IIA, was present in 84.9% of patients. There was no hospital mortality or major postoperative complication. The mean operative time was 65 min, intensive care unit stay was 22 ± 5 h, and postoperative hospital stay was 7.5 ± 1.7 days. Conclusion Thoracoscopic thymectomy for thymoma in Vietnamese patients achieved improved cosmesis and was safe for both non-myasthenia gravis and myasthenia gravis patients.


Subject(s)
Thymectomy/methods , Thymoma/surgery , Adult , Aged , Female , Humans , Length of Stay , Male , Middle Aged , Operative Time , Thoracic Surgery, Video-Assisted/adverse effects , Thymectomy/adverse effects , Thymoma/diagnosis , Time Factors , Treatment Outcome , Vietnam , Young Adult
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