Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
Department of Chemistry, COMSATS University Islamabad, Abbottbad Campus 22060, Pakistan.
Bioorg Med Chem. 2018 Jul 23;26(12):3654-3663. doi: 10.1016/j.bmc.2018.05.046. Epub 2018 May 26.
Inhibition of Thymidine phosphorylase (TP) is continuously studied for the design and development of new drugs for the treatment of neoplastic diseases. As a part of our effort to identify TP inhibitors, we performed a structure-based virtual screening (SBVS) of our compound collection. Based on the insights gained from structures of virtual screening hits, a scaffold was designed using 1,3,4-oxadiazole as the basic structural feature and SAR studies were carried out for the optimization of this scaffold. Twenty-five novel bis-indole linked 1,3,4-oxadiazoles (7-31) were designed, synthesized and tested in vitro against E. coli TP (EcTP). Compound 7 emerged as potent TP inhibitor with an IC value of 3.50 ± 0.01 μM. Docking studies were carried out using GOLD software on thymidine phosphorylase from human (hTP) and E. coli (EcTP). Various hydrogen bonding, hydrophobic interactions, and π-π stacking were observed between designed molecules and the active site amino acid residues of the studied enzymes.
胸苷磷酸化酶（TP）的抑制作用一直是设计和开发治疗肿瘤疾病的新药的研究重点。作为我们识别 TP 抑制剂努力的一部分，我们对我们的化合物库进行了基于结构的虚拟筛选（SBVS）。基于虚拟筛选命中结构的见解，使用 1,3,4-恶二唑作为基本结构特征设计了一个支架，并对该支架进行了 SAR 研究以进行优化。设计、合成并测试了 25 种新型双吲哚连接的 1,3,4-恶二唑（7-31），以评估其对大肠杆菌 TP（EcTP）的体外抑制活性。化合物 7 表现出较强的 TP 抑制活性，IC 值为 3.50 ± 0.01 μM。使用 GOLD 软件对来自人（hTP）和大肠杆菌（EcTP）的胸苷磷酸化酶进行了对接研究。在设计的分子与研究酶的活性位点氨基酸残基之间观察到各种氢键、疏水相互作用和 π-π 堆积。
