Delineation of the molecular mechanisms of nucleoside recognition by cytidine deaminase through virtual screening.
Delineation of the molecular mechanisms of nucleoside recognition by cytidine deaminase through virtual screening.
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DOI：
10.1002/cmdc.201100139
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发表时间：
2011-08-01
期刊：
影响因子：
3.4
通讯作者：
Vincenzetti, Silvia
中科院分区：
文献类型：
--
作者：
Costanzi, Stefano;Vilar, Santiago;Micozzi, Daniela;Carpi, Francesco M.;Ferino, Giulio;Vita, Alberto;Vincenzetti, Silvia
胞苷脱氨酶（3.5.4.5，CDA）是嘧啶补救途径的一种酶，负责几种基于胞苷的抗肿瘤药物（如阿糖胞苷、吉西他滨、地西他滨和氮杂胞苷）的降解和失活。因此，高度寻求CDA抑制剂作为与所述药物共同施用的化合物以改善其有效性。另外，抗肿瘤药物的设计不受CDA的作用也被认为是一个有吸引力的解决方案。在这里，我们描述了一个虚拟筛选CDA配体的化学相似性和分子对接的基础上。该活动导致鉴定出三种新型抑制剂和一种新型底物，命中率为19%，并允许显着扩展结构-活性关系，也考虑到导致非活性的化合物。通过筛选确定的最具活性的化合物是抑制剂假异胞苷，其具有作为高度稳定化合物的先导的潜力。该研究还描述了5-氮杂和6-氮杂取代的不利影响，3′-位存在氨基的不相容性，以及2′-阿拉伯糖位周围存在非常严格的空间要求，甚至N4-位。重要的是，这些功能可以用于设计新的抗CDA作用的药物。
Cytidine deaminase (3.5.4.5, CDA), an enzyme of the pyrimidine salvage pathways, is responsible for the degradation and inactivation of several cytidine-based antitumoral drugs, such as cytarabine, gemcitabine, decitabine, and azacytidine. Thus, CDA inhibitors are highly sought after as compounds to be co-administered with said drugs in order to improve their effectiveness. Alternatively, the design of antitumoral drugs not susceptible to the action of CDA is also regarded as an attractive solution. Here, we describe a virtual screening for CDA ligands based on chemical similarity and molecular docking. The campaign led to identification of three novel inhibitors and one novel substrate, with a 19% hit rate, and allowed a significant extension of the structure-activity relationships, also in light of the compounds that resulted inactive. The most active compound identified through the screening was the inhibitor pseudoisocytidine, which has the potential to serve as a lead for highly stable compounds. The study also delineated the detrimental effect of 5-aza and 6-aza substitutions, the incompatibility of the presence of an amino group at the 3′-position, as well as the presence of very strict steric requirements around the 2′-arabino position and, even more, the N4-position. Importantly, these features can be exploited for the design of novel antineoplastic agents resistant to the action of CDA.
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影响因子：
2.9
作者：
Costanzi, Stefano;Vincenzetti, Silvia;Vita, Alberto
通讯作者：
Vita, Alberto
影响因子：
3
作者：
Beumer, Jan H.;Eiseman, Julie L.;Gilbert, Judith A.;Holleran, Julianne L.;Yellow-Duke, Archibong E.;Clausen, Dana M.;D'Argenio, David Z.;Ames, Matthew M.;Hershberger, Pamela A.;Parise, Robert A.;Bai, Lihua;Covey, Joseph M.;Egorin, Merrill J.
通讯作者：
Egorin, Merrill J.
DOI：
10.1021/ci010132r
发表时间：
2002-11-01
期刊：
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
影响因子：
--
作者：
Durant, JL;Leland, BA;Nourse, JG
通讯作者：
Nourse, JG
DOI：
10.1093/protein/gzg117
发表时间：
2003-12-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Vincenzetti, S;De Sanctis, G;Vita, A
通讯作者：
Vita, A
影响因子：
1.6
作者：
Vincenzetti, S;Cambi, A;Vita, A
通讯作者：
Vita, A