Abordagem em bioquímica quântica aplicados à modulação de SIRT6 e PIM1: desvendando novas estratégias terapêuticas com flavonoides

Abstract

Metabolic diseases and cancers affect millions of people worldwide, representing a health and well-being problem for society. In this scenario, two proteins, SIRT6 and PIM1, emerge. These macromolecules have stood out as potential therapeutic targets for these pathologies since their regulatory functions are directly associated with preventing these diseases. SIRT6 is an NAD+-dependent deacylase, and its activation has potential against metabolic and aging-related diseases. In contrast, its inhibition is considered promising in cancer therapy. The investigation of the modulation of this protein by specific molecules stands out as a promising area. PIM1 is a proto-oncogene overexpressed in several types of human cancer, and its inhibition is considered a promising target for cancer therapy. Here, we explore the modulation of SIRT6 with the flavonoids quercetin (QUE) and its derivative isoquercetin (ISO), in addition to catechin gallate (GC) and trichostanin-A (TSA), as well as the PIM1 protein with the flavonoids quercetin (QUE), myricetin (MYC) and pentahydroxyflavone (PTH), providing a detailed view of the molecular interactions that lead to the activation and/or inhibition of these proteins. For this, we used computational methods from the perspective of Molecular Modeling through the Molecular Fractionation with Conjugated Caps (MFCC) technique in accordance with the calculation parameters of the Density Functional Theory (DFT). These evaluations were carried out within a radius of up to 10.0 Å away from the modulators. The energy analysis of the SIRT6-modulator complex demonstrated that the activating substances (GC) and (TSA) were more expressive compared to the inhibitory molecules (QUE) and (ISO). In contrast, for the PIM1-inhibitor complex, the flavonoid that presented the most expressive interaction was (PTH) followed by (QUE) and (MYC). Our results provide relevant evidence for the rational development of new drugs targeting SIRT6 and PIM1 with the potential to impact the regulation of these proteins and open perspectives in the research of new therapeutic approaches for metabolic diseases and cancer.