Repurposing Clinical Drugs as AdoMetDC Inhibitors Using the SCAR Strategy

Abstract

With the escalating costs in drug development, discovering new uses of approved drugs, i.e., drug repurposing, has attracted increasing interest. Spermidine and spermine are important polyamines for most cells and their biosynthesis are strictly regulated by the polyamine metabolic network. In cancerous cells and tumor environments, the concentrations of polyamines are much higher than in normal cells. During the synthesis of spermidine and spermine, an amino-propyl group is provided by decarboxylated S-adenosylmethionine, and the latter is generated from S-adenosylmethionine by AdoMetDC (AdoMet decarboxylase). Therefore, as a ratelimiting enzyme in the biosynthesis of spermidine and spermine, AdoMetDC has been an attractive drug target in cancer studies. In the last decades, many AdoMetDC inhibitors have been discovered, and several AdoMetDC inhibitors are under clinical trials, but unfortunately, none of them have been approved yet. To overcome the high costs in time and money for discovering de novo inhibitors, we set out to repurpose clinic drugs as AdoMetDC inhibitors. We used steric-clashes alleviating receptors (SCAR), a computer-aided drug discovery strategy developed by us recently for in silico screening. By combining computational screening and experimental validation, we successfully identified two approved drugs that have inhibitory potency on AdoMetDC's enzymatic activity. SCAR was previously shown to be suitable for the discovery of both covalent and non-covalent inhibitors, and this work further demonstrated the value of the SCAR strategy in drug repurposing.

The rational discovery of multipurpose inhibitors of the ornithine decarboxylase

“…2 Therefore, it is of great value to find inhibitors that can inhibit the polyamine levels. 20,36,37 In this work, we used ODC as an example to assess the value of targeting ISPs with multipurpose ligands. ODC is an ISP in the polyamine metabolic network, and it is the rate-limiting enzyme in polyamine synthesis and regulated by both homodimerization and the binding of OAZ1.…”

“…Previous studies confirmed that polyamine contents are significantly elevated in many cancers 2 . Therefore, it is of great value to find inhibitors that can inhibit the polyamine levels 20,36,37 . In this work, we used ODC as an example to assess the value of targeting ISPs with multipurpose ligands.…”

Potential clinical drugs as covalent inhibitors of the priming proteases of the spike protein of SARS-CoV-2

“…Therefore, as the other similar proteases [33] , targeting these priming proteases might be an effective choice to disrupt the infection of this virus. Based on our recent work [17] , [19] , [20] , we adopted the SCARdock protocol to repurpose clinic drugs as potential inhibitors of these priming proteases in this study. We identified several clinic drugs that might be useful as the covalent inhibitors of CatB, CatL, and TMPRSS2.…”

“…To help the discovery of covalent drugs, we previously established a “steric-clashes alleviating receptor (SCAR)” strategy [17] for the in silico docking and screening of covalent drugs enlightened by in silico protein design [18] . More recently, we demonstrated that our SCARdock method is also useful in drug repurposing [19] , [20] .…”

Potential covalent drugs targeting the main protease of the SARS-CoV-2 coronavirus

“…Realizing the potential use of SCAR in discovering both covalent and non-covalent inhibitors, we recently demonstrated that SCAR is also quite efficient in drug repurposing (Y. Zhang et al, 2020). Compared with non-covalent drugs, covalent drugs have the following advantages (Mah et al, 2014): (i) covalent drugs have better biochemical efficiency since they are more competitive than many non-covalent endogenous substrates and cofactors; (ii) covalent drugs cause lower patient burden and delay the emergence of drug resistance due to lower and less frequent dosing; (iii) covalent drugs might have better target specificity by reacting with a non-conserved nucleophilic amino acid with careful designs (Cuesta et al, 2020).…”