Bonito Cátia A, Ferreira Ricardo J, Ferreira Maria-José U, Durães Fernando, Sousa Emília, Gillet Jean-Pierre, Cordeiro M Natália D S, Dos Santos Daniel J V A
LAQV@REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, Porto 4169-007, Portugal.
Red Glead Discovery AB, Medicon Village, Scheelevägen 8, Lund 223 63, Sweden.
ACS Omega. 2023 Mar 14;8(12):11281-11287. doi: 10.1021/acsomega.2c08273. eCollection 2023 Mar 28.
A medicinal chemistry approach combining and methodologies was performed aiming at identifying and characterizing putative allosteric drug-binding sites (aDBSs) at the interface of the transmembrane- and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified, one in TMD1/NBD1 and another one in TMD2/NBD2, by means of fragment-based molecular dynamics and characterized in terms of size, polarity, and lining residues. From a small library of thioxanthone and flavanone derivatives, experimentally described to bind at the TMD-NBD interfaces, several compounds were identified to be able to decrease the verapamil-stimulated ATPase activity. An IC of 81 ± 6.6 μM is reported for a flavanone derivative in the ATPase assays, providing evidence for an allosteric efflux modulation in P-glycoprotein. Molecular docking and molecular dynamics gave additional insights on the binding mode on how flavanone derivatives may act as allosteric inhibitors.
采用结合了[具体方法1]和[具体方法2]的药物化学方法，旨在识别和表征P-糖蛋白跨膜结构域与核苷酸结合结构域（TMD-NBD）界面处假定的变构药物结合位点（aDBSs）。通过基于片段的分子动力学在TMD1/NBD1中识别出一个aDBS，在TMD2/NBD2中识别出另一个aDBS，并从大小、极性和内衬残基方面对其进行了表征。从一个实验证明能结合在TMD-NBD界面的噻吨酮和黄烷酮衍生物的小库中，鉴定出几种能够降低维拉帕米刺激的ATP酶活性的化合物。在ATP酶测定中，一种黄烷酮衍生物的IC为81±6.6μM，这为P-糖蛋白中的变构外排调节提供了证据。分子对接和分子动力学对黄烷酮衍生物如何作为变构抑制剂的结合模式提供了更多见解。
