“…It catalyzes the conversion of AdoMet to dcAdoMet (Fig. 1a), and the latter is exclusively utilized for providing propyl amines for the synthesis of spermidine and spermine8141516. Therefore, AdoMetDC can be inhibited to decrease the level of polyamines in cancerous cells, and one AdoMetDC inhibitor, SAM486A, showed promising results in clinic trials192021.…”
Section: Discussionmentioning
confidence: 99%
“…A rate-limiting reaction in the polyamine biosynthetic pathway is the generation of decarboxylated S-adenosyl-L-methionine (dcAdoMet, or dcSAM) from S–adenosylmethionine (AdoMet, or SAM), which is catalyzed by S-adenosylmethionine decarboxylase (AdoMetDC, or SAMDC; EC 4.1.1.50). AdoMetDC catalyzes the removal of the carboxyl group from AdoMet, and the product dcAdoMet is exclusively used for the biosynthesis of spermidine and spermine813141516. High levels of polyamines are detected in many human diseases including various tumors, so AdoMetDC has long been an attractive drug target, and a variety of AdoMetDC inhibitors have been developed81214151718.…”
mentioning
confidence: 99%
“…AdoMetDC catalyzes the removal of the carboxyl group from AdoMet, and the product dcAdoMet is exclusively used for the biosynthesis of spermidine and spermine813141516. High levels of polyamines are detected in many human diseases including various tumors, so AdoMetDC has long been an attractive drug target, and a variety of AdoMetDC inhibitors have been developed81214151718. One AdoMetDC inhibitor, SAM486A (4-amidinoindan-1-one-2 ′ -amidinohydrazone, also named as CGP48664), has been shown to be promising in Phase I and II human clinical trials, but the side effects unrelated to the inhibition of AdoMetDC have been observed192021.…”
mentioning
confidence: 99%
“…This radioactive assay is precise, but has a huge limitation due to the involvement of 14 C-labeled substrates, trapping of 14 CO 2 , and resource intensive detection procedures. This limitation becomes a burden especially when it comes to experimental HTP screening of AdoMetDC inhibitors813141516. Although the high-performance liquid chromatography (HPLC) analysis of the other product, dcAdoMet, is an effective alternative method8121415171833, it is also quite complicated and not suitable for HTP screening.…”
Natural polyamines are small polycationic molecules essential for cell growth and development, and elevated level of polyamines is positively correlated with various cancers. As a rate-limiting enzyme of the polyamine biosynthetic pathway, S-adenosylmethionine decarboxylase (AdoMetDC) has been an attractive drug target. In this report, we present the discovery of novel human AdoMetDC (hAdoMetDC) inhibitors by coupling computational and experimental tools. We constructed a reasonable computational structure model of hAdoMetDC that is compatible with general protocols for high-throughput drug screening, and used this model in in silico screening of hAdoMetDC inhibitors against a large compound library using a battery of computational tools. We also established and validated a simple, economic, and non-radioactive enzymatic assay, which can be adapted for experimental high-throughput screening of hAdoMetDC inhibitors. Finally, we obtained an hAdoMetDC inhibitor lead with a novel scaffold. This study provides both new tools and a new lead for the developing of novel hAdoMetDC inhibitors.
“…It catalyzes the conversion of AdoMet to dcAdoMet (Fig. 1a), and the latter is exclusively utilized for providing propyl amines for the synthesis of spermidine and spermine8141516. Therefore, AdoMetDC can be inhibited to decrease the level of polyamines in cancerous cells, and one AdoMetDC inhibitor, SAM486A, showed promising results in clinic trials192021.…”
Section: Discussionmentioning
confidence: 99%
“…A rate-limiting reaction in the polyamine biosynthetic pathway is the generation of decarboxylated S-adenosyl-L-methionine (dcAdoMet, or dcSAM) from S–adenosylmethionine (AdoMet, or SAM), which is catalyzed by S-adenosylmethionine decarboxylase (AdoMetDC, or SAMDC; EC 4.1.1.50). AdoMetDC catalyzes the removal of the carboxyl group from AdoMet, and the product dcAdoMet is exclusively used for the biosynthesis of spermidine and spermine813141516. High levels of polyamines are detected in many human diseases including various tumors, so AdoMetDC has long been an attractive drug target, and a variety of AdoMetDC inhibitors have been developed81214151718.…”
mentioning
confidence: 99%
“…AdoMetDC catalyzes the removal of the carboxyl group from AdoMet, and the product dcAdoMet is exclusively used for the biosynthesis of spermidine and spermine813141516. High levels of polyamines are detected in many human diseases including various tumors, so AdoMetDC has long been an attractive drug target, and a variety of AdoMetDC inhibitors have been developed81214151718. One AdoMetDC inhibitor, SAM486A (4-amidinoindan-1-one-2 ′ -amidinohydrazone, also named as CGP48664), has been shown to be promising in Phase I and II human clinical trials, but the side effects unrelated to the inhibition of AdoMetDC have been observed192021.…”
mentioning
confidence: 99%
“…This radioactive assay is precise, but has a huge limitation due to the involvement of 14 C-labeled substrates, trapping of 14 CO 2 , and resource intensive detection procedures. This limitation becomes a burden especially when it comes to experimental HTP screening of AdoMetDC inhibitors813141516. Although the high-performance liquid chromatography (HPLC) analysis of the other product, dcAdoMet, is an effective alternative method8121415171833, it is also quite complicated and not suitable for HTP screening.…”
Natural polyamines are small polycationic molecules essential for cell growth and development, and elevated level of polyamines is positively correlated with various cancers. As a rate-limiting enzyme of the polyamine biosynthetic pathway, S-adenosylmethionine decarboxylase (AdoMetDC) has been an attractive drug target. In this report, we present the discovery of novel human AdoMetDC (hAdoMetDC) inhibitors by coupling computational and experimental tools. We constructed a reasonable computational structure model of hAdoMetDC that is compatible with general protocols for high-throughput drug screening, and used this model in in silico screening of hAdoMetDC inhibitors against a large compound library using a battery of computational tools. We also established and validated a simple, economic, and non-radioactive enzymatic assay, which can be adapted for experimental high-throughput screening of hAdoMetDC inhibitors. Finally, we obtained an hAdoMetDC inhibitor lead with a novel scaffold. This study provides both new tools and a new lead for the developing of novel hAdoMetDC inhibitors.
“…Fig. 2The current preclinical applications of the Pheroid® and pro-Pheroid® technology under investigation [5,[18], [19], [20], [21], [22], [23], [24], [25], [26]]. …”
The Apicomplexa parasite Plasmodium is a major cause of death in developing countries which are less equipped to bring new medicines to the market. Currently available drugs used for treatment of malaria are limited either by inadequate efficacy, toxicity and/or increased resistance. Availability of the genome sequence, microarray data and metabolic profile of Plasmodium parasite offers an opportunity for the identification of stage-specific genes important to the organism's lifecycle. In this study, microarray data were analysed for differential expression and overlapped onto metabolic pathways to identify differentially regulated pathways essential for transition to successive erythrocytic stages. The results obtained indicate that S-adenosylmethionine decarboxylase/ornithine decarboxylase, a bifunctional enzyme required for polyamine synthesis, is important for the Plasmodium cell growth in the absence of exogenous polyamines. S-adenosylmethionine decarboxylase/ornithine decarboxylase is a valuable target for designing therapeutically useful inhibitors. One such inhibitor, [Formula: see text]-difluoromethyl ornithine, is currently in use for the treatment of African sleeping sickness caused by Trypanosoma brucei. Structural studies of ornithine decarboxylase along with known inhibitors and their analogues were carried out to screen drug databases for more effective and less toxic compounds.
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