Binding mode analysis of dual inhibitors of human thymidylate synthase and dihydrofolate reductase as antitumour agents via molecular docking and DFT studies
MetadataShow full item record
Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases. Nevertheless, to design multitarget inhibitors is concurrently a great challenge for medicinal chemists. Human thymidylate synthase (hTS) and human dihydrofolate reductase (hDHFR) are the key enzymes in folate metabolic pathway that is necessary for the biosynthesis of RNA, DNA and protein. Their inhibition has found clinical utility as antitumour, antimicrobial and antiprotozoal agents. The aim of this study is to elucidate the factors which are responsible for the potent inhibition of hTS and hDHFR, respectively, through the detailed analysis of the binding modes of dual TS-DHFR inhibitors at both active sites using molecular docking study. Moreover, this study is also accompanied by the exploration of electronic features of dual inhibitors via the density functional theory approach. This study demonstrates that appropriate substitution at the sixth position of thieno[2,3-d]pyrimidines moiety in non-classical dual inhibitors of hTS and hDHFR plays a key role in the inhibition of hTS and hDHFR enzymes. In general, the outcomes of this research exertion will significantly be helpful in drug design for cancer chemotherapy.
Showing items related by title, author, creator and subject.
An Innovative Strategy for Dual Inhibitor Design and Its Application in Dual Inhibition of Human Thymidylate Synthase and Dihydrofolate Reductase EnzymesArooj, Mahreen; Sakkiah, Sugunadevi; Ping Cao, Guang; Woo Lee, Keun (2013)Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases. Nevertheless, ...
Yudi, M.; Farouque, O.; Andrianopoulos, N.; Ajani, A.; Brennan, A.; Lefkovits, J.; Reid, Christopher; Chan, W.; Duffy, S.; Clark, D.; Melbourne Interventional Group. (2017)BACKGROUND: The optimal time to administer P2Y12 inhibitors in patients with ST-elevation myocardial infarction (STEMI) remains to be defined. We sought to assess whether a pretreatment strategy was associated with improved ...
Baxter, Fiona O. (2001)This thesis reports structure-function assessments made using site-directed mutagenesis of the human enzyme 5alpha-reductase (5AR), an enzyme crucial for normal masculine development. These assessments utilised the ...