In Search for Inhibitors of Human Aldo-Keto Reductase 1B10 (AKR1B10) as Novel Agents to Fight Cancer and Chemoresistance: Current State-of-the-Art and Prospects

Review

作者: Ottanà, Rosaria ; Maccari, Rosanna

Aldo-keto reductase 1B10 (AKR1B10) is a human enzyme that catalyzes the NADPH-dependent reduction of several different carbonyl compounds to the corresponding alcohols. Under physiological conditions, AKR1B10 is expressed mainly in the gastrointestinal tract, where it can detoxify reactive carbonyl compounds derived from dietary sources and xenobiotics. AKR1B10 is highly expressed in several cancers and precancerous conditions, proving to be crucially implicated in carcinogenesis and to function as a prognostic indicator of tumor development. Moreover, AKR1B10 up-regulation is strictly related to acquired resistance to known anticancer drugs. High levels of this enzyme are also correlated to the pathogenesis of noncancerous diseases, such as skin pathologies and COVID-19 complications. Therefore, in the last two decades, AKR1B10 has attracted interest as a novel target for agents able to fight both cancer and chemoresistance, and here, it is explored from a medicinal chemistry perspective.

2023-10-13·Journal of Biomolecular Structure and Dynamics

Quantum chemical studies on the binding domain of SARS-CoV-2 S-protein: human ACE2 interface complex

Article

作者: Suresh, Cherumuttathu H. ; Haritha, Mambatta

A two-layer ONIOM(B3LYP/6-31G*:PM7) method is used to model the binding of several drug/drug-like molecules (L) at the SARS-CoV-2 S-protein: human ACE2 protein interface cavity. The selected molecules include a set of thirty-five ligands from the study of Smith and Smith which showed a high docking score in the range of -7.0 to -7.7 kcal/mol and another set of seven repurposing drugs, viz. favipiravir, remdesivir, EIDD, galidesivir, triazavirin, ruxolitinib, and baricitinib. The ONIOM model of the cavity (M) showed a highly polarized electron distribution along its top-to-bottom direction while Ls with lengths in the range 1.0 - 1.5 nm fitted well inside the cavity in a head-to-tail fashion to yield ML complexes. The ligands showed a large variation in the ONIOM-level binding energy (E_b), in the range -2.7 to -85.4 kcal/mol. The E_b of ML complexes better than -40.0 kcal/mol is observed for myricetin, fidarestat, protirelin, m-digallic acid, glucogallin, benserazide hydrochlorideseradie, remdesivir, tazobactum, sapropterin, nitrofurantoin, quinonoid, pyruvic acid calcium isoniazid, and aspartame, and among them the highest E_b -85.4 kcal/mol is observed for myricetin. A hydroxy substitution is suggested for the phenyl ring of aspartame to improve its binding behavior at the cavity, and the resulting ligand 43 showed the best E_b -84.5 kcal/mol. The ONIOM-level study is found to be effective for the interpretation of the noncovalent interactions resulting from residues such as arginine, histidine, tyrosine, lysine, carboxylate, and amide moieties in the active site and suggests rational design strategies for COVID-19 drug development.Communicated by Ramaswamy H. Sarma.

2023-02-01·Reproductive Sciences

Comparative Evaluation of Aldose Reductase Inhibition in Polycystic Ovarian Syndrome–Induced Rats

Article

作者: Patel, Roshni ; Deshpande, Shrikalp ; Pathak, Zarna ; Shah, Gaurang

Polycystic ovary syndrome (PCOS) represents a spectrum of disorders, associated with hyperandrogenism, oligoanovulation, and polycystic ovaries. Aldose reductase (AR), a rate-limiting enzyme of polyol pathway, is responsible for maintenance of intracellular osmotic balance, facilitation of oocyte development, and organization of the granulosa cells in the ovary. Cyclic changes in the aldose reductase level were found during the 4-5 days estrus cycle in rat, which is regulated by gonadotropin-releasing hormone (GnRH). Irregular GnRH secretion in PCOS patients may lead to altered aldose reductase expression and ovarian dysfunction. Treatment with a novel AR inhibitor, fidarestat, has been reported to improve erythrocyte sorbitol content in diabetic patients. Hence, the potential role AR in pathogenesis of PCOS was investigated by inhibiting AR with fidarestat in PCOS-induced rats. Pre-pubertal female Sprague-Dawley rats were divided into five groups. PCOS is induced either by administering letrozole or by feeding high-fat diet for 90 days. After induction of PCOS, fidarestat treatment was given for 28 days and various parameters were measured. In PCOS-induced rats, parameters like food intake, body weight, insulin, OGTT, triglycerides, cholesterol, prolonged diestrus phase, ovary weight, and immunohistological localization AR were found to be significantly altered. Fidarestat treatment significantly improved ovary weight, ovarian aldose reductase localization in PCOS-induced rats. Improvement in all these parameters suggest involvement of aldose reductase in the pathogenesis of PCOS.

100 项与非达司他相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D01842	非达司他	-	DB02021

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
糖尿病性神经病变	临床3期	美国	Sanwa Kagaku Kenkyusho Co., Ltd.	-
糖尿病性神经病变	临床3期	欧洲	-	-
周围神经系统疾病	临床3期	-	Daiichi Sankyo Co., Ltd.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ARVO2008	N/A	糖尿病并发症	-	Low-dose fidarestat (8 mg/kg/day)	(鏇鬱範糧餘襯築鬱廠鏇) = 糧製範齋窪艱鑰膚鏇獵壓遞築淵網餘糧構廠廠 (鹽窪築願構鹽壓窪鏇夢 ) 更多	-	2008-05-01
				High-dose fidarestat (32 mg/kg/day)	(鏇鬱範糧餘襯築鬱廠鏇) = 鏇遞淵鹽憲願膚窪願齋壓遞築淵網餘糧構廠廠 (鹽窪築願構鹽壓窪鏇夢 ) 更多
ARVO2004	N/A	糖尿病并发症	-	Fidarestat 16 mg/kg/day	(顧鹹衊願鏇餘廠餘鑰夢) = 製鏇顧網網廠齋網廠憲蓋窪鹹膚鬱顧襯膚壓鹽 (積糧壓選網簾選廠鏇醖 ) 更多	-	2004-05-01
				Fidarestat (Untreated)	(網鬱範顧廠遞壓夢壓糧) = 顧築簾窪鹽鹽遞鹹遞夢廠蓋鬱廠選廠顧繭築糧 (網淵鹹夢範壓鹽遞築膚 ) 更多