ArticleBioorganic & medicinal chemistry letters2019
Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.
Article in Bioorganic & medicinal chemistry letters, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 51 citations in OpenAlex.
- Structure-Based Screening Identifies Polyphenol Glucuronides as Cyclophilin D Ligands.Molecules (Basel, Switzerland) · 2026Article
- Article
- Structural and Kinetic Variability of Pathogen Cyclophilins: Functional Diversification and Therapeutic Potential.ACS infectious diseases · 2026Review
- Efficient Binding Affinity Estimation for Fragment-Based Compounds Using a Separated Topologies Approach.Journal of chemical information and modeling · 2026Article
- Pushing the limits of hydrogen/deuterium exchange mass spectrometry to study protein:fragment low affinity interactions.Communications chemistry · 2025Article
- Potent Preorganized Pyrazolidine Cyclophilin D Inhibitors Prevent Mitochondrial and Organ Injury in a Mouse Pancreatitis Disease Model.Journal of medicinal chemistry · 2025Article
- Article
- Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments.Journal of medicinal chemistry · 2025Article
- Toward Dual Targeting of Catalytic and Gatekeeper Pockets in Cyclophilins Using a Macrocyclic Scaffold.ACS medicinal chemistry letters · 2024Article
- Neuroprotective Effect of 2-(Benzyloxy)arylureas Is Not Related to CypD Inhibition nor Suppression of mPTP Opening.ACS medicinal chemistry letters · 2024Article
- Automated Adaptive Absolute Binding Free Energy Calculations.Journal of chemical theory and computation · 2024Article
- Tuning Potential Functions to Host-Guest Binding Data.Journal of chemical theory and computation · 2024Article
- A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1.International journal of molecular sciences · 2023Article
- Extract2Chip-Bypassing Protein Purification in Drug Discovery Using Surface Plasmon Resonance.Biosensors · 2023Article
- Halo Library, a Tool for Rapid Identification of Ligand Binding Sites on Proteins Using Crystallographic Fragment Screening.Journal of medicinal chemistry · 2023Article
- Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates.RSC medicinal chemistry · 2022Article
- Discovery and molecular basis of subtype-selective cyclophilin inhibitors.Nature chemical biology · 2022Article
- Non-Immunosuppressive Cyclophilin Inhibitors.Angewandte Chemie (International ed. in English) · 2022Review
- Article
- Evaluating the use of absolute binding free energy in the fragment optimisation process.Communications chemistry · 2022Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.