8CNH

Crystal structure of human soluble adenylyl cyclase (sAC) in complex with inhibitor TDI-10512

Summary for 8CNH

• Entry DOI: 10.2210/pdb8cnh/pdb
• Descriptor: Adenylate cyclase type 10, methyl 2-[[3-(2-azanyl-6-chloranyl-pyrimidin-4-yl)-1-methyl-pyrazol-4-yl]methyl]benzoate, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: camp, adenylyl cyclase, inhibitor, catalytic domain, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 55635.78

Authors

Steegborn, C. (deposition date: 2023-02-23, release date: 2023-04-26, Last modification date: 2024-10-23)

Primary citation

Sun, S.,Fushimi, M.,Rossetti, T.,Kaur, N.,Ferreira, J.,Miller, M.,Quast, J.,van den Heuvel, J.,Steegborn, C.,Levin, L.R.,Buck, J.,Myers, R.W.,Kargman, S.,Liverton, N.,Meinke, P.T.,Huggins, D.J.
Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.
J.Chem.Inf.Model., 63:2828-2841, 2023

PubMed Abstract: Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout. We employed free energy perturbation to first scaffold hop to a preferable chemotype and then optimize the binding affinity to sub-nanomolar levels while retaining druglike properties. The results illustrate that effective use of free energy perturbation can enable a drug discovery campaign to progress rapidly from hit to lead, facilitating proof-of-concept studies that enable target validation.

PubMed: 37060320
DOI: 10.1021/acs.jcim.2c01577

Experimental method

X-RAY DIFFRACTION (2 Å)