Virtual screening, structure based pharmacophore mapping, and molecular simulation studies of pyrido[2,3-d]pyrimidines as selective thymidylate synthase inhibitors

Article

作者: Singh, Ankit Kumar ; Verma, Amita ; Pathak, Prateek ; Thareja, Suresh ; Grishina, Maria ; Kumar, Pradeep ; Singh, Harshwardhan ; Novak, Jurica ; Kumar, Adarsh

Human thymidylate synthase is the rate-limiting enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate. dUMP (pyrimidine) and folate binding site hTS inhibitors showed resistance in colorectal cancer (CRC). In the present study, we have performed virtual screening of the pyrido[2,3-d]pyrimidine database, followed by binding free energy calculations, and pharmacophore mapping to design novel pyrido[2,3-d]pyrimidine derivatives to stabilize inactive confirmation of hTS. A library of 42 molecules was designed. Based on the molecular docking studies, four ligands (T36, T39, T40, and T13) were identified to have better interactions and docking scores with the catalytic sites [dUMP (pyrimidine) and folate binding sites] of hTS protein than standard drug, raltitrexed. To validate efficacy of the designed molecules, we performed molecular dynamics simulation studies at 1000 ns with principal component analysis and binding free energy calculations on the hTS protein, also drug likeness properties of all hits were in acceptable range. Compounds T36, T39, T40, and T13 interacted with the catalytic amino acid (Cys195), an essential amino acid for anticancer activity. The designed molecules stabilized the inactive conformation of hTS, resulting in the inhibition of hTS. The designed compounds will undergo synthesis and biological evaluation, which may yield selective, less toxic, and highly potent hTS inhibitors.Communicated by Ramaswamy H. Sarma.

2022-07-01·Bioorganic Chemistry2区 · 化学

Novel 2-arylthiazolidin-4-one-thiazole hybrids with potent activity against Mycobacterium tuberculosis

2区 · 化学

Article

作者: Othman, Dina I A ; Hamdi, Abdelrahman ; Abdel-Aziz, Marwa M ; Elfeky, Sherin M

Substituted aldehydes, ethyl 2-(2-amino-thiazol-4-yl)acetate), and 2-mercaptoacetic acid, in a three-component one-pot green synthetic approach afforded 2-arylthiazolidin-4-one- thiazole hybrids(T1-T13). Compounds showed good anti-tubercular activity towards sensitive M. tuberculosis strain. Compound T8 was as potent as isoniazide (INH) with MIC = 0.12 μg/ml. Compounds T2 and T13 showed potent activity with MIC = 0.48 μg/ml. Other compounds showed moderate to good anti-tubercular activity towards MDR M. tuberculosis strain with MIC range 1.95-125 μg/ml. Compounds T2, T8, T9, and T13 showed anti-tubercular activity towards XDR M. tuberculosis strain with MIC range 7.81-125 μg/ml. Compounds T2 and T8 were capable of inhibiting M. tuberculosis InhA enzyme in-vitro with IC₅₀ = 1.3 ± 0.61 µM and 1.06 ± 0.97 µM, respectively. Molecular docking simulation showed that T2 and T8 were also capable of interacting at the catalytic site of InhA enzyme in a similar mode to the native ligand through binding with NAD⁺ and Tyr158. The 3D- QSAR study highlighted the relevance of substitution of phenyl group at position-2 of thiazolidin-4-one where bulky electronegative substitution at position-4 of the phenyl ring favored the activity against M. tuberculosis H37R. Additionally, compounds showed good antibacterial activity against bronchitis causing bacteria M. pneumoniae, S. pneumonia, K. pneumonia, and B. pertussis compared to Azithromycin. In-silico studies of ADMET descriptors and drug-likeness were conducted for all synthesized compounds. Compounds showed good oral bioavailability, good gastrointestinal absorption and showed no signs of adverse effects to the liver or CNS. Compounds showed no potential carcinogenicity as well.

2014-01-01·Bioorganic & Medicinal Chemistry3区 · 医学

The synthesis of novel taxoids for oral administration

3区 · 医学

Article

作者: Jing, Yun-rong ; Zhou, Wei ; Li, Wan-liang ; Zhao, Lin-xiang ; Wang, Yong-feng

A group of novel taxoids, with modifications at C-7, C-10, C-3' and C-14 positions of paclitaxel, was synthesized in order to improve their biological profile by decreasing their affinity with P-glycoprotein (P-gp) and increasing cellular permeability. Most of the new taxoids demonstrated the similar potent cytotoxic activities in MCF-7 human tumor cell line as paclitaxel in vitro. In the permeability assay with monolayers of Caco-2 cells, most of the compounds demonstrated an increased trans-cellular transport in A-to-B direction in comparison with paclitaxel. Among them the compounds T-13, T-15 and T-26 showed the highest permeability, and with efflux ratios better than that of ortataxel. The interaction of the compounds T-13 and T-26 with P-gp was evaluated using Madin-Darby canine kidney (MDCK)-multidrug resistance-1(MDR1) and MDCK-wild-type (WT). The results indicated that T-13 and T-26 were poor substrates for P-gp and possessed inhibiting effects of P-gp mediated efflux. It was thus clear that simultaneous modifications at the C-7, C-10 and C-3' positions of paclitaxel significantly impaired its interactions with P-gp and interfered with P-gp mediated efflux.

100 项与 T-13 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
糖尿病	药物发现	中国	贵州百灵企业集团制药股份有限公司	-
糖尿病	药物发现	中国	四川大学华西医院（四川省国际医院）	-