Metastable states and spectroscopic parameters of PI3K enzyme inhibitors: biased simulations and quantum calculations for early cancer diagnosis

Abstract

Cancer affects the life of many people worldwide. Not only by the severe symptoms, which can lead the patient to death, but also due to the high cost of the treatments. One of the major contributions for the presented problem lies in the fact that the early diagnosis of the mentioned disease is of great complexity, reducing the chances of a successful treatment or intervention.

Hence, the use of spectroscopic probes, like fluorescent sensors, with imaging clinical exami- nation, shows to be a good strategy for enhancing the early stage diagnosis of the mentioned

illness. Nowadays, there is a range of molecules available for such a task, being based on pho- tophysical phenomena like the Excited State Intramolecular Proton Transfer (ESIPT). Despite

that, there are few works studying metastable states effects on the ESIPT fluorescence. There- fore, the present study main goal was to investigate how different conformations in a state of no- nequilibrium affects the ESIPT fluorescence of the 2-(2’-hidroxi-4’-aminophenyl)benzothiazole

(HABT), a molecule of the class of the phenylbenzothiazoles (PBTs). Thereunto, two biased

MD simulations were carried out, obtaining the trajectory files for further analysis with the Prin- cipal Component Analysis (PCA). The three systems studied were: HABT only (1), HABT in

water reservoir (2) and HABT anchored in protein PI3K in the presence of water (3). Therewith, it was observed how the solvent and protein anchoring affects the access of metastable states of the HABT molecule, in which they were characterized in conformational terms. It was observed that, by considering a nonequilibrium state and the interactions between the HABT molecule with PI3K protein, the most part of the accessed conformations were capable of performing the ESIPT process. Therefore, by bringing the complexity of a nonequilibrium approach for

modelling a biological system, being this perspective of great importance in modern drug de- velopment, the present study sheds light on the performance of the proposed sensor in early

cancer diagnosis. In that regard, the present work significantly contributes to the search for bet- ter solutions for cancer disease, in which it was shown to be possible to use the nonequilibrium

approach in order to propose new fluorescent sensors for disease diagnosis.