8/12/2023 0 Comments Hsp90 a molecular chaperone![]() Therefore, it was hypothesized that a highly selective HSP90beta inhibitor should impair spermatogenesis without undesired effects. Testis-specific HSP90beta inhibition induces apoptosis in the testis. The computational simulation results provide a possible reason for the higher affinities of ouabain and its analogues for the rat alpha4 compare to the rat alpha1 isoform. His118 and Asn129 of Loop1 of the rat alpha4 isoform stabilize the compound-enzyme complex more dynamically than the corresponding amino acid residues of the rat alpha1 isoform. Computational simulations including homology modeling, molecular docking, MM-GBSA calculations, and MD simulations were employed to investigate the structural origin of their selectivity. Ouabain, SS-I-24, SS-I-42, and SS-I-54 are highly selective inhibitors of the rat alpha4 over the rat alpha1 isoform. In vitro assay results reveal that cetirizine is a selective Na,K-ATPase alpha4 inhibitor that reduces sperm motility and has the potential to be a promising scaffold for male contraceptive development. Based on subsequent docking screening cetirizine was identified as a potential Na,K-ATPase alpha4 binder. In search for additional chemical matter a HTVS was performed to identify selective inhibitors of the Na,K-ATPase alpha4 following homology modeling of the Na,K-ATPase alpha4. It binds ouabain with a higher affinity than other Na,K-ATPase alpha isoforms, and provides the opportunity to pharmacologically target the Na,K-ATPase alpha4 for male contraception. Na,K-ATPase alpha4 is specifically expressed in male germ cells of the testis and abundant in the sperm flagellum, and crucial for sperm motility.
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