RESUMEN

The 5-Hydroxytryptamine (5HT)-2A receptor, a key target in psychoactive drug development, presents significant challenges in the design of selective compounds. Here, we describe the construction, evaluation and validation of two machine learning (ML) models for the classification of bioactivity mechanisms against the (5HT)-2A receptor. Employing neural networks and XGBoost models, we achieved an overall accuracy of around 87 %, which was further enhanced through molecular modelling (MM) (e.g. molecular dynamics simulations) and binding free energy analysis. This ML-MM integration provided insights into the mechanisms of direct modulators and prodrugs. A significant outcome of the current study is the development of a 'binding free energy fingerprint' specific to (5HT)-2A modulators, offering a novel metric for evaluating drug efficacy against this target. Our study demonstrates the prospective of employing a successful workflow combining AI with structural biology, offering a powerful tool for advancing psychoactive drug discovery.

Asunto(s)

Aprendizaje Automático , Simulación de Dinámica Molecular , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2A/metabolismo , Humanos , Unión Proteica , Termodinámica , Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular

RESUMEN

Introduction: "Meaning" and "happiness" are leading topics in positive psychology, but their relationship is not well understood. The first step to better understanding is to inspect the pattern of correlations found in the research literature. Specifically, we seek answers to the following questions of fact: (1) Is there a correlation between perceived meaning of life and satisfaction with life? (2) If so, is that correlation positive or negative? (3) How strong is this correlation? (4) How variable is this correlation across persons and situations? (5) Do the correlations differ across components of happiness? (6) What aspects of meaning are most/least associated with happiness? (7) What sources of meaning are most/least associated with happiness? (8) Does seeing meaning relate differently to happiness than searching for meaning? Method: We took stock of the available research findings, using the World Database of Happiness, which holds standardized descriptions of 171 observed relations between perceived meaning of life and satisfaction with life. Results: We found strong correlations between happiness and the degree of perceived meaning in life but little correlation with the pursuit of meaning. While the correlation with the degree of meaning is positive at the micro-level of individuals, it appears to be negative at the macro-level of nations. Discussion: Having established the above mentioned matters of fact, we considered the following questions on causality: (1) Is there an innate need for meaning? (2) How does the perceived meaning of life otherwise affect satisfaction with life? (3) How does satisfaction with life affect the perceived the meaning of life? (4) Why is the correlation positive at the micro-level of individuals, but negative at the macro-level of nations? Conclusions: We conclude that there is no innate human need for meaning. Still, the perceived meaning of life can affect life satisfaction in various other ways, while life satisfaction will also affect the sense of meaning. Both positive and negative effects can be involved, the balance of which tends to be positive for seeing meaning but close to neutral for pursuing meaning.