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Identification of novel selective Mtb ‐DHFR inhibitors as antitubercular agents through structure‐based computational techniques
Archiv der Pharmazie ( IF 5.1 ) Pub Date : 2019-12-23 , DOI: 10.1002/ardp.201900287
Kalicharan Sharma 1 , Nazia Neshat 1 , Shweta Sharma 1 , Namita Giri 2 , Apeksha Srivastava 1 , Faisal Almalki 3 , Khalid Saifullah 3 , Md Mumtaz Alam 1 , Mohammad Shaquiquzzaman 1 , Mymoona Akhter 1, 4
Affiliation  

Inhibition of dihydrofolate reductase from Mycobacterium tuberculosis‐dihydrofolate reductase (Mtb‐DHFR) has emerged as a promising approach for the treatment of tuberculosis. To identify novel Mtb‐DHFR inhibitors, structure‐based virtual screening (SBVS) of the Molecular Diversity Preservation International (MolMall) database was performed using Glide against the Mtb‐DHFR and h‐DHFR enzymes. On the basis of SBVS, receptor fit, drug‐like filters, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, 16 hits were selected and tested for their antitubercular activity against the H37RV strain of M. tuberculosis. Five compounds showed promising activity with compounds 11436 and 15275 as the most potent hits with IC50 values of 0.65 and 12.51 μM, respectively, against the H37RV strain of M. tuberculosis. The two compounds were further tested in the Mtb‐DHFR and h‐DHFR enzymatic assay for selectivity and were found to be three‐ to eight‐fold selective towards Mtb‐DHFR over h‐DHFR with minimum inhibitory concentration values of 5.50, 73.89 µM and 42.00, 263.00 µM, respectively. In silico simulation studies also supported the stability of the protein–ligand complex formation. The present study demonstrates the successful utilization of in silico SBVS tools for the identification of novel and potential Mtb‐DHFR inhibitors and compound 11436 ((2,4‐dihydroxyphenyl)(3,4,5‐trihydroxyphenyl)methanone) as a potential lead for the development of novel Mtb‐DHFR inhibitors.

中文翻译:

通过基于结构的计算技术鉴定新型选择性 Mtb-DHFR 抑制剂作为抗结核药物

抑制结核分枝杆菌二氢叶酸还原酶 (Mtb-DHFR) 中的二氢叶酸还原酶已成为治疗结核病的一种有前途的方法。为了鉴定新型 Mtb-DHFR 抑制剂,使用 Glide 对 Mtb-DHFR 和 h-DHFR 酶进行了分子多样性保护国际 (MolMall) 数据库的基于结构的虚拟筛选 (SBVS)。在 SBVS、受体拟合、类药物过滤器和 ADMET(吸收、分布、代谢、排泄和毒性)分析的基础上,选择了 16 个命中并测试了它们对结核分枝杆菌 H37RV 菌株的抗结核活性。五种化合物显示出有希望的活性,其中化合物 11436 和 15275 作为最有效的命中物,对结核分枝杆菌的 H37RV 菌株的 IC50 值分别为 0.65 和 12.51 μM。在 Mtb-DHFR 和 h-DHFR 酶促测定中进一步测试了这两种化合物的选择性,发现对 Mtb-DHFR 的选择性是 h-DHFR 的三到八倍,最小抑制浓度值为 5.50、73.89 µM 和分别为 42.00、263.00 µM。计算机模拟研究也支持蛋白质-配体复合物形成的稳定性。本研究表明成功利用计算机 SBVS 工具识别新型和潜在的 Mtb-DHFR 抑制剂和化合物 11436((2,4-二羟基苯基)(3,4,5-三羟基苯基)甲酮)作为潜在的先导物新型 Mtb-DHFR 抑制剂的开发。
更新日期:2019-12-23
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