5OCI

Human Heat Shock Protein 90 bound to 6-Hydroxy-3-(3-methyl-benzyl)-1H-indazole-5-carboxylic acid methyl-(4-morpholin-4-yl-phenyl)-amide

Summary for 5OCI

• Entry DOI: 10.2210/pdb5oci/pdb
• Descriptor: Heat shock protein HSP 90-alpha, 6-Hydroxy-3-(3-methyl-benzyl)-1H-indazole-5-carboxylic acid methyl-(4-morpholin-4-yl-phenyl)-amide (3 entities in total)
• Functional Keywords: heat-shock protein complex, hsp90, atpase, pyrazole, chaperone, atp-binding, heat shock, nucleotide-binding, phosphorylation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 26170.36

Authors

Schuetz, D.A.,Richter, L.,Amaral, M.,Grandits, M.,Musil, D.,Graedler, U.,Frech, M.,Ecker, G.F. (deposition date: 2017-07-03, release date: 2018-05-23, Last modification date: 2024-05-08)

Primary citation

Schuetz, D.A.,Richter, L.,Amaral, M.,Grandits, M.,Gradler, U.,Musil, D.,Buchstaller, H.P.,Eggenweiler, H.M.,Frech, M.,Ecker, G.F.
Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors.
J. Med. Chem., 61:4397-4411, 2018

PubMed Abstract: Residence time and more recently the association rate constant k are increasingly acknowledged as important parameters for in vivo efficacy and safety of drugs. However, their broader consideration in drug development is limited by a lack of knowledge of how to optimize these parameters. In this study on a set of 176 heat shock protein 90 inhibitors, structure-kinetic relationships, X-ray crystallography, and molecular dynamics simulations were combined to retrieve a concrete scheme of how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant k decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand that point toward a hydrophobic cavity. We validated this scheme by increasing polarity of three Hsp90 inhibitors and observed a 9-, 13-, and 45-fold slowdown of on-rates and a 9-fold prolongation in residence time. This prolongation was driven by transition state destabilization rather than ground state stabilization.

PubMed: 29701469
DOI: 10.1021/acs.jmedchem.8b00080

Experimental method

X-RAY DIFFRACTION (1.62 Å)