Free Ligand 1D NMR Conformational Signatures To Enhance Structure Based Drug Design of a Mcl-1 Inhibitor (AZD5991) and Other Synthetic Macrocycles.

Journal of Medicinal Chemistry
Amber Y S BalazsElisabetta Chiarparin

Abstract

The three-dimensional conformations adopted by a free ligand in solution impact bioactivity and physicochemical properties. Solution 1D NMR spectra inherently contain information on ligand conformational flexibility and three-dimensional shape, as well as the propensity of the free ligand to fully preorganize into the bioactive conformation. Herein we discuss some key learnings, distilled from our experience developing potent and selective synthetic macrocyclic inhibitors, including Mcl-1 clinical candidate AZD5991. Case studies have been selected from recent oncology research projects, demonstrating how 1D NMR conformational signatures can complement X-ray protein-ligand structural information to guide medicinal chemistry optimization. Learning to extract free ligand conformational information from routinely available 1D NMR signatures has proven to be fast enough to guide medicinal chemistry decisions within design cycles for compound optimization.

References

Aug 5, 2006·Nature Reviews. Drug Discovery·Robert A CopelandThomas D Meek
Apr 7, 2007·Journal of Chemical Information and Modeling·Dimitris K AgrafiotisEric Martin
Oct 8, 2009·Journal of Chemical Information and Modeling·Pascal BonnetEric Martin
Jul 28, 2013·Bioorganic & Medicinal Chemistry·Charles D BlundellAndrew Almond
Oct 24, 2013·Angewandte Chemie·Heike Schönherr, Tim Cernak
Nov 5, 2013·Drug Discovery Today·Harry Finch
Jan 3, 2016·Drug Discovery Today. Technologies·Franz-Josef Meyer-Almes
Jan 3, 2016·Drug Discovery Today. Technologies·Andreas Schoop, Fabian Dey
Feb 9, 2016·Progress in Medicinal Chemistry·Charles D BlundellMartin J Watson
Apr 14, 2016·Advanced Drug Delivery Reviews·Pär MatssonJan Kihlberg
Feb 16, 2017·ACS Medicinal Chemistry Letters·Jeffrey W JohannesAlexander W Hird
May 10, 2017·Bioorganic & Medicinal Chemistry Letters·Yajun ZhengSuresh B Singh
Jul 21, 2017·Journal of Chemical Information and Modeling·Dan SindhikaraShana L Posy
Aug 8, 2017·Drug Discovery Today·Rutger H A Folmer
Sep 18, 2017·Trends in Biochemical Sciences·Stefano Gianni, Per Jemth
Nov 10, 2017·Journal of Chemical Theory and Computation·Haoyu S YuLingle Wang
Apr 3, 2018·Journal of Medicinal Chemistry·Matteo Rossi SebastianoJan Kihlberg
Apr 24, 2018·Progress in Medicinal Chemistry·Sulejman AlihodžićDinko Žiher
Jan 17, 2019·Future Medicinal Chemistry·Elisabetta ChiarparinDavid M Wilson

❮ Previous
Next ❯

Citations

Mar 4, 2020·Expert Opinion on Therapeutic Patents·Yi-Min LiuJing-Ping Liou
Jul 29, 2020·Journal of Biomolecular NMR·Abhinav DubeyHaribabu Arthanari
Jul 4, 2020·Journal of Biomolecular NMR·Reto HorstJane M Withka
Aug 18, 2020·Journal of Computer-aided Molecular Design·Anikó UdvarhelyiRainer Wilcken
Mar 24, 2021·Journal of the American Chemical Society·Shinya KoboriAndrei K Yudin
Jul 28, 2020·Bioorganic & Medicinal Chemistry Letters·Neil P GrimsterScott D Edmondson
May 14, 2021·Journal of Medicinal Chemistry·Paul D LeesonAndrew R Leach
Jul 2, 2021·Organic & Biomolecular Chemistry·Piotr RauboMorgan Thomas
Oct 31, 2019·Journal of Medicinal Chemistry·Neal J Zondlo
Oct 14, 2021·Journal of Chemical Theory and Computation·João MoradoChris-Kriton Skylaris
Nov 18, 2021·Journal of Medicinal Chemistry·Gabriele FumagalliDavid R Spring

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.