Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry01:29

Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry

5.4K
Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.
5.4K
Prochirality02:05

Prochirality

4.8K
The concept of prochirality leads to the nomenclature of the individual faces of a molecule and plays a crucial role in the enantioselective reaction. It is a concept where two or more achiral molecules react to produce chiral products. A typical process is the reaction of an achiral ketone to generate a chiral alcohol. Here, the achiral reactant reacts with an achiral reducing agent, sodium borohydride, to generate an equimolar mixture of the chiral enantiomers of the product. For example, an...
4.8K
Regioselectivity of Electrophilic Additions to Alkenes: Markovnikov's Rule02:17

Regioselectivity of Electrophilic Additions to Alkenes: Markovnikov's Rule

16.1K
If a set of reactants can yield multiple constitutional isomers, but one of the isomers is obtained as the major product, the reaction is said to be regioselective. In such reactions, bond formation or breaking is favored at one reaction site over others.
The hydrohalogenation of an unsymmetrical alkene can yield two haloalkane products, depending on which vinylic carbon takes up the halogen. However, one product usually predominates, where hydrogen adds to the vinylic carbon bearing the...
16.1K
Stability of Substituted Cyclohexanes02:30

Stability of Substituted Cyclohexanes

14.7K
This lesson discusses the stability of substituted cyclohexanes with a focus on energies of various conformers and the effect of 1,3-diaxial interactions.
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
14.7K
Regioselectivity and Stereochemistry of Hydroboration02:36

Regioselectivity and Stereochemistry of Hydroboration

9.3K
A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
9.3K
Diels–Alder Reaction Forming Cyclic Products: Stereochemistry01:28

Diels–Alder Reaction Forming Cyclic Products: Stereochemistry

4.7K
The Diels–Alder reaction is one of the robust methods for synthesizing unsaturated six-membered rings. The reaction involves a concerted cyclic movement of six π electrons: four π electrons from the diene and two π electrons from the dienophile.
4.7K

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Multiscale Neural Network Potential with Anisotropic Message Passing for the Fast and Accurate Simulation of Protein Dynamics and Enzymatic Reactions.

Journal of the American Chemical Society·2026
Same author

Balancing Data Quantity and Quality: Evaluating Curation Strategies for Bioactivity Prediction in Lead Optimization.

Journal of chemical information and modeling·2026
Same author

Editorial: Expanding horizons in stress research-innovative paradigms and new directions in 2025.

Neurobiology of stress·2026
Same author

Pharmacological Inhibition of FKBP51 Mitigates Early Life Adversity-Induced Social Deficits in Male Mice.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)·2026
Same author

Protocol for validating drug efficacy and safety in scalable 96-well platforms of human cortical organoids and melanoma brain metastases.

STAR protocols·2026
Same author

Human organoids: Fit for drug discovery?

Stem cell reports·2026
Same journal

Library Docking for Cannabinoid-2 Receptor Ligands.

Journal of medicinal chemistry·2026
Same journal

Charting New Territory: Systematic Evaluation of the Drug Potential of <i>N</i>-Trifluoromethyl Amides, Ureas & Carbamates.

Journal of medicinal chemistry·2026
Same journal

Red-Light-Triggered <i>In Vitro</i> and <i>In Vivo</i> Photocatalytic Cancer Therapy with Polypyridyl Os(II) Photocatalysts.

Journal of medicinal chemistry·2026
Same journal

Novel Selenium-Containing Small Molecule PD-L1 Inhibitors: Design, Synthesis, and Evaluation of the Antitumor Activity.

Journal of medicinal chemistry·2026
Same journal

HsClpP-Engaging Selective Mitochondrial Pan-PDK Degraders for Cancer Therapy.

Journal of medicinal chemistry·2026
Same journal

Rational Development of Activatable Prodrugs of the GSTP1 Inhibitor NBDHEX: Turn-On NIR Fluorogenic Drug Delivery with Selective Anticancer Activity.

Journal of medicinal chemistry·2026
See all related articles

Related Experiment Video

Updated: Jan 10, 2026

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors
09:45

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors

Published on: April 27, 2017

11.1K

Linker Modification Enables Control of Key Functional Group Orientation in Macrocycles.

Christian Brudy1, Enrico Ruijsenaars2, Christian Meyners1

  • 1Department of Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Peter-Grünberg-Straße 4, 64287 Darmstadt, Germany.

Journal of Medicinal Chemistry
|November 22, 2025
PubMed
Summary
This summary is machine-generated.

Macrocyclic drug modifications enhance binding affinity and stability. Small changes, like adding a methyl group, significantly improve properties for targeting FKBP51, a key stress response regulator.

More Related Videos

Solid-phase Synthesis of [4.4] Spirocyclic Oximes
05:15

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

Published on: February 6, 2019

7.2K
Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy
07:36

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

Published on: November 9, 2019

8.4K

Related Experiment Videos

Last Updated: Jan 10, 2026

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors
09:45

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors

Published on: April 27, 2017

11.1K
Solid-phase Synthesis of [4.4] Spirocyclic Oximes
05:15

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

Published on: February 6, 2019

7.2K
Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy
07:36

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

Published on: November 9, 2019

8.4K

Area of Science:

  • Medicinal Chemistry
  • Structural Biology
  • Pharmacology

Background:

  • Macrocycles offer unique conformational preorganization for drug development.
  • Understanding how scaffold modifications impact preorganization is crucial but poorly explored.

Purpose of the Study:

  • To investigate how macrocyclization and linker derivatization influence conformational preorganization.
  • To optimize macrocyclic drug properties such as affinity, selectivity, and stability.
  • To develop macrocycles targeting FKBP51 for stress response modulation.

Main Methods:

  • Synthesized and derivatized macrocyclic compounds.
  • Utilized high-resolution cocrystal structures for structural analysis.
  • Performed molecular dynamics simulations to understand conformational changes.
  • Assessed binding affinity, selectivity, plasma stability, brain permeability, and solubility.

Main Results:

  • A single methyl group on the macrocyclic scaffold increased binding affinity up to 10-fold.
  • Derivatization of the linker region fine-tuned carbonyl group orientation, improving properties.
  • Developed highly ligand-efficient macrocycles with good brain permeability and solubility.
  • Demonstrated a promising in vivo profile for FKBP51 inhibition.

Conclusions:

  • Minor modifications to macrocyclic scaffolds can significantly enhance drug properties.
  • Macrocycles allow for precise tuning of conformational preorganization via linker modifications.
  • This approach yields potent and stable macrocyclic drugs with potential therapeutic applications, exemplified by FKBP51 targeting.