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Developing a computational method to calculate pH-dependent membrane permeabilities for anti-tumour drugs
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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.
Descrição
Tese de Mestrado, Bioquímica, 2022, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Bases de Lewis CpHMD Umbrella Sampling Fármacos anti-tumorais Difusão Membranar Teses de mestrado - 2022