| Full text | |
| Author(s): |
Neto, Xisto Antonio de Oliveira
[1]
;
Alves, Anna Carolina Schneider
[1, 2]
;
Dias Junior, Reinaldo Antonio
[3]
;
Rodrigues, Ricardo Pereira
[4]
;
Lancellotti, Marcelo
[1, 2]
;
Almeida, Wanda Pereira
[1, 2]
;
Kawano, Daniel Fabio
[3, 1, 2]
Total Authors: 7
|
| Affiliation: | [1] Univ Campinas UNICAMP, Fac Pharmaceut Sci, BR-13083871 Campinas, SP - Brazil
[2] Rodrigues, Ricardo Pereira, Univ Espirito Santo UFES, Hlth Sci Ctr CCS, Dept Pharmaceut Sci, BR-29047105 Vitoria, ES, Brazil.Neto, Xisto Antonio de Oliveira, Univ Campinas UNICAMP, Fac Pharmaceut Sci, BR-13083871 Campinas, SP - Brazil
[3] Univ Campinas UNICAMP, Inst Chem, BR-13083970 Campinas, SP - Brazil
[4] Univ Espirito Santo UFES, Hlth Sci Ctr CCS, Dept Pharmaceut Sci, BR-29047105 Vitoria, ES - Brazil
Total Affiliations: 4
|
| Document type: | Journal article |
| Source: | EUROPEAN JOURNAL OF LIPID SCIENCE AND TECHNOLOGY; v. 122, n. 7 JUN 2020. |
| Web of Science Citations: | 0 |
| Abstract | |
Alkylphospholipids are synthetic analogues of endogenous phosphatidylcholines with a remarkable ability: induce the selective apoptosis of exponentially growing tumor cells. One hypothesis concerning their mechanism of action is the inhibition of cytidine triphosphate:phosphocholine cytidyltransferase (CCT), which would significantly suppress the phosphatidylcholine biosynthesis to trigger apoptosis. Herein, homology modeling, docking simulations, and the analyses of molecular interaction fields are used to suggest the most probable binding modes of four alkylphospholipids (edelfosine, erucylphosphocholine, perifosine, and miltefosine) and lysophosphatidylcholine at the catalytic domain of human CCT. All compounds display bind modes in agreement with the corresponding groups found in the CCT substrate, phosphocholine, while their binding strengths are increased because of the interaction of the alkyl chains with hydrophobic residues from the M domain of the protein. Analyses of the geometry of the CCT binding-site also suggest that small groups, such as benzyl/2-phenylethyl ethers or equivalent heterocycles, could replace the O-methyl group in edelfosine to yield even better inhibitors. It is believed this study can guide the development of new alkylphospholipids with an improved profile for the inhibition of phosphatidylcholine biosynthesis, a critical component for cell cycle progression that can be explored in cancer chemotherapy. Practical Applications: Studies focusing on the interactions between small ligands and their protein targets are decisive for the comprehension of how conformational changes in the macromolecular structure dictates the biological activity and, consequently, how they can be explored in drug discovery. Most of the current studies on alkylphospholipids focuses on their physicochemical interactions with cholesterol and sphingolipids in lipid rafts that, because of the variability and complexity of the membrane phases, hardly can provide structural data in the X-ray crystallography assays necessary for molecular modeling studies. Therefore, by exploring the inhibition of human cytidine triphosphate:phosphocholine cytidyltransferase as an alternative and, probably, complementary hypothesis to the membrane rafts, a helpful strategy can be provided to overcome the clinical limitations of alkylphospholipids. (AU) | |
| FAPESP's process: | 18/08585-1 - Design and synthesis of new phospholipids that selectively induce the apoptosis of tumor cells via lipid rafts |
| Grantee: | Daniel Fábio Kawano |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 18/22817-2 - Synthesis of new antitumor phospholipids as inhibitors of the human enzyme cytidine triphosphate (CTP): phosphocholine cytidylyltransferase |
| Grantee: | Xisto Antonio de Oliveira Neto |
| Support Opportunities: | Scholarships in Brazil - Master |
| FAPESP's process: | 17/05876-2 - Design and synthesis of new phospholipids that selectively induce the apoptosis of tumor cells via lipid rafts |
| Grantee: | Anna Carolina Schneider Alves |
| Support Opportunities: | Scholarships in Brazil - Doctorate |