8coj | pdb_00008coj
Crystal structure of human soluble adenylyl cyclase catalytic domain in complex with the inhibitor TDI-10228
Structural highlights
DiseaseADCYA_HUMAN Idiopathic hypercalciuria. Disease susceptibility is associated with variations affecting the gene represented in this entry. FunctionADCYA_HUMAN Soluble adenylyl cyclase that has a critical role in mammalian spermatogenesis. Produces the cAMP which mediates in part the cAMP-responsive nuclear factors indispensable for maturation of sperm in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. May be the bicarbonate sensor. Involved in ciliary beat regulation.[1] [2] Publication Abstract from PubMedFree 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. Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.,Sun S, Fushimi M, Rossetti T, Kaur N, Ferreira J, Miller M, Quast J, van den Heuvel J, Steegborn C, Levin LR, Buck J, Myers RW, Kargman S, Liverton N, Meinke PT, Huggins DJ J Chem Inf Model. 2023 Apr 15. doi: 10.1021/acs.jcim.2c01577. PMID:37060320[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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