Publicação
Developing a computational method to calculate pH-dependent membrane permeabilities for anti-tumour drugs
| datacite.subject.fos | Ciências Naturais::Ciências Químicas | pt_PT |
| dc.contributor.advisor | Machuqueiro, Miguel Ângelo dos Santos | |
| dc.contributor.author | Suzano, Pedro Miguel Sousa | |
| dc.date.accessioned | 2022-07-13T13:24:12Z | |
| dc.date.available | 2022-07-13T13:24:12Z | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022 | |
| dc.description | Tese de Mestrado, Bioquímica, 2022, Universidade de Lisboa, Faculdade de Ciências | pt_PT |
| dc.description.abstract | The tumor micro-environment is characterized by increased acidity, that can change the prolonalion of some chemotherapeutic drugs and, conseq uently, their ove rall so lubility. Some of these compounds are Lewis bases that enter cells by membrane passive diffu sio n. In waler, Lhey are charged (as their pKa val ue is above phys iological pH) and a neulralization/deprotonation occurs in the membrane-crossing process. In this work, we aim to quantify the effect or prolonalion in Ihe membrane permeabi lity of sun ilinib and ninledanib al th ree pH values: pH=4.5 to mode l the acidic lysosomal interior, pH=6.0 to model the ac idic exterior of tumor cells and pH=7.S 10 mimic the phys iological pH of healthy cells. A di fference between healthy and tumor cells should be obtained by comparing pH=6.0 with pH=7.S. Results from pH=4.S can provide insight regarding the lyso somal sequestration phenomenon that has been proposed as a drug res istance mechanism. The US-CpHMD method was applied to these pH environments and permeability calculations were performed . The method proved to be very robust in esti mating pH effects in the membrane permeabi lity of both drugs. We observed that even though nintedanib crosses the membrane throu gh pass ive diffu sion only slightly disturbed by low pH, suni ti nib is heavily impaired by acidity. This behavior at lower pH values ind icates that sunit inib, and probably other Lewis bases wi th similar polarity/protonation profiles, ]X)ssesses a d ear preference for healthy cells, compared with tumors, and a high propensity to be entrapped within Iysosomes wi th lillIe to no poss ibil ity of escaping. These findings may explain sun itinib high toxicity and the susceptibility 10 drug resistance in chemotherapeutic reg imes. Futu re research regardi ng the titra ble group of sunitinib and other structurally similar Lewis bases is imperative in the design of pH-specific anti -tumor drugs. | pt_PT |
| dc.identifier.tid | 203217535 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10451/53778 | |
| dc.language.iso | eng | pt_PT |
| dc.subject | Bases de Lewis | pt_PT |
| dc.subject | CpHMD | pt_PT |
| dc.subject | Umbrella Sampling | pt_PT |
| dc.subject | Fármacos anti-tumorais | pt_PT |
| dc.subject | Difusão Membranar | pt_PT |
| dc.subject | Teses de mestrado - 2022 | pt_PT |
| dc.title | Developing a computational method to calculate pH-dependent membrane permeabilities for anti-tumour drugs | pt_PT |
| dc.type | master thesis | |
| dspace.entity.type | Publication | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | masterThesis | pt_PT |
| thesis.degree.name | Mestrado em Bioquímica | pt_PT |