6ZND
[1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2 Inhibitors
Summary for 6ZND
| Entry DOI | 10.2210/pdb6znd/pdb |
| Descriptor | cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | pde2a inhibitor, fep, sbdd, free energy perturbation, molecular dynamics, alzheimers disease, phosphodiesterase, molecular design, binding free energy, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 83839.03 |
| Authors | Tresadern, G.,Leonard, P.M. (deposition date: 2020-07-06, release date: 2020-07-22, Last modification date: 2024-01-31) |
| Primary citation | Tresadern, G.,Velter, I.,Trabanco, A.A.,Van den Keybus, F.,Macdonald, G.J.,Somers, M.V.F.,Vanhoof, G.,Leonard, P.M.,Lamers, M.B.A.C.,Van Roosbroeck, Y.E.M.,Buijnsters, P.J.J.A. [1,2,4]Triazolo[1,5- a ]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration. J.Med.Chem., 63:12887-12910, 2020 Cited by PubMed Abstract: We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC's from 2340 to 0.89 nM. Lead compound originating from the FEP calculations showed PDE2A inhibition IC of 1.3 ± 0.39 nM, ∼100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, target occupancy, and promise for further lead optimization. PubMed: 33105987DOI: 10.1021/acs.jmedchem.0c01272 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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