8COT

Complex of human soluble adenylyl cyclase 10 catalytic core with inhibitor TDI-10962

8COT の概要

• エントリーDOI: 10.2210/pdb8cot/pdb
• 分子名称: Adenylate cyclase type 10, 2-(dimethylamino)ethyl 5-(2-azanyl-6-chloranyl-pyrimidin-4-yl)-2-methyl-4-(phenylmethyl)pyrazole-3-carboxylate, DIMETHYL SULFOXIDE, ... (6 entities in total)
• 機能のキーワード: camp, sac, inhibitor complex, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55540.58

構造登録者

Steegborn, C.,Fushimi, M. (登録日: 2023-02-28, 公開日: 2023-04-26, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)