Merging Allosteric and Active Site Binding Motifs: De novo Generation of Target Selectivity and Potency via Natural‐Product‐Derived Fragments

Lanz, Jan; Riedl, Rainer

doi:10.1002/cmdc.201402478

Cited by 37 publications

(36 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The Riedl laboratory has synthesized potent and selective MMP‐13 inhibitors that combine the selectivity originating from population of the selectivity loop with the gain in potency resulting from metal chelation . Compound 55 (Figure ) resulted from de novo design in which the natural‐product‐derived core fragment, uracil, was placed into the S1′ pocket of MMP‐13.…”

Section: Mmp Inhibitorsmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug‐discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small‐molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X‐ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure‐based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.

show abstract

Section: Mmp Inhibitorsmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

“…Once the structure of a target or a co‐crystal structure of a target together with a bound ligand is available, structure‐based design can be applied both rationally and creatively in order to tailor the properties of a drug molecule. Fragment‐based approaches are used for the identification of chemical starting points for lead optimization, virtual docking allows in silico screening, and de novo approaches generate new chemotypes for drug molecules 4, 5, 6, 7, 8…”

Section: Introductionmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

Self Cite

View full text Add to dashboard Cite

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

show abstract

“…However, important pharmacokinetic (PK) and/or other data have not been reported for many of these compounds, and no clinical studies have appeared. For example, no PK or MSS data has been reported for the Aventis and Wyeth compounds . The first series of Pfizer compounds, while exhibiting good PK and MSS data, were tested against a limited number of MMPs .…”

Section: Mmp Inhibitors: General Considerationsmentioning

confidence: 99%

Clinical Implications of Compounds Designed to Inhibit ECM‐Modifying Metalloproteinases

2017

View full text Add to dashboard Cite

Remodeling of the extracellular matrix (ECM) is crucial in development and homeostasis, but also has a significant role in disease progression. Two metalloproteinase families, the matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs), participate in the remodeling of the ECM, either directly or through the liberation of growth factors and cell surface receptors. The correlation of MMP and ADAM activity to a variety of diseases has instigated numerous drug development programs. However, broad-based and Zn -chelating MMP and ADAM inhibitors have fared poorly in the clinic. Selective MMP and ADAM inhibitors have been described recently based on (a) antibodies or antibody fragments or (b) small molecules designed to take advantage of protease secondary binding sites (exosites) or allosteric sites. Clinical trials have been undertaken with several of these inhibitors, while others are in advanced pre-clinical stages.

show abstract

Merging Allosteric and Active Site Binding Motifs: De novo Generation of Target Selectivity and Potency via Natural‐Product‐Derived Fragments

Cited by 37 publications

References 47 publications

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Targeting Antibiotic Resistance

Clinical Implications of Compounds Designed to Inhibit ECM‐Modifying Metalloproteinases

Contact Info

Product

Resources

About