Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(18), С. 12651 - 12677

Опубликована: Сен. 6, 2023

Target-based drug discovery is the dominant paradigm of discovery; however, a comprehensive evaluation its real-world efficiency lacking. Here, manual systematic review about 32000 articles and patents dating back to 150 years ago demonstrates apparent inefficiency. Analyzing origins all approved drugs reveals that, despite several decades dominance, only 9.4% small-molecule have been discovered through "target-based" assays. Moreover, therapeutic effects even this minimal share cannot be solely attributed reduced their purported targets, as they depend on numerous off-target mechanisms unconsciously incorporated by phenotypic observations. The data suggest that reductionist target-based may cause productivity crisis in discovery. An evidence-based approach enhance seems prioritizing, selecting optimizing molecules, higher-level observations are closer sought-after using tools like artificial intelligence machine learning.

Язык: Английский

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Reduction, Emergence and the Metaphysics in Science

Опубликована: Фев. 18, 2025

Язык: Английский

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Neurocognitive Mechanisms

Oxford University Press eBooks, Год журнала: 2020, Номер unknown

Опубликована: Ноя. 12, 2020

Abstract This book provides the foundations for a neurocomputational explanation of cognition based on contemporary cognitive neuroscience. An ontologically egalitarian account composition and realization, according to which all levels are equally real, is defended. Multiple realizability mechanisms explicated in light this framework. A goal-contribution teleological functions defended, so mechanistic version functionalism. foundation computation, turn clarifies ways computational theory multilevel supported by The argues that at least generic sense. defended from standard objections yet priori arguments rebutted. contends typical vehicles neural computations representations that, contrary received view, observable manipulable laboratory. also neither digital nor analog; instead, sui generis. concludes investigating relation between computation consciousness, suggesting consciousness may have functional not wholly nature.

Язык: Английский

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Grounding cognition: heterarchical control mechanisms in biology

Philosophical Transactions of the Royal Society B Biological Sciences, Год журнала: 2021, Номер 376(1820), С. 20190751 - 20190751

Опубликована: Янв. 25, 2021

We advance an account that grounds cognition, specifically decision-making, in activity all organisms as autonomous systems must perform to keep themselves viable—controlling their production mechanisms. Production mechanisms, we characterize them, activities such procuring resources from environment, putting these use construct and repair the organism's body moving through environment. Given variable nature of environment continual degradation organism, mechanisms be regulated by control select when a is required how it should carried out. To operate on need procure information measurement processes evaluate possible actions. They are making decisions. In organisms, decisions made multiple different organized not hierarchically but heterarchically. many cases, they employ internal models features with which organism deal. Cognition, form thus fundamental living This article part theme issue ‘Basal cognition: conceptual tools view single cell’.

Язык: Английский

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Philosophy of Neuroscience

Опубликована: Фев. 8, 2022

This Element provides a comprehensive introduction to philosophy of neuroscience. It covers such topics as how neuroscientists procure knowledge, including not just research techniques but the use various model organisms. presents examples knowledge acquired in neuroscience that are then employed discuss more philosophical nature explanations developed neuroscience, different conception levels discussions and invocation representations explanations. The text emphasizes importance brain processes beyond those neocortex explores what makes processing different. consider view nervous system consists control mechanisms considers arguments for hierarchical vs. heterarchical organization mechanisms. concludes by considering implications findings humans conceive themselves practices embracing norms.

Язык: Английский

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Understanding Multicellularity: The Functional Organization of the Intercellular Space

Frontiers in Physiology, Год журнала: 2019, Номер 10

Опубликована: Сен. 18, 2019

The aim of this paper is to provide a theoretical framework understand how multicellular systems realise functionally integrated physiological entities by organising their intercellular space. From perspective centred on physiology and integration, biological are often characterised as organised in such way that they metabolic self-production self-maintenance. existence activity components rely the network continuous management exchange matter energy with environment. One virtues organismic approach focused organisation it can an understanding into coherent wholes. Organismic frameworks have been primarily developed focusing unicellular life. Multicellularity, however, presents additional challenges our systems, related cells capable live together higher-order entities, some features behaviours constrained controlled system realise. Whereas most accounts multicellularity focus cell differentiation increase size main elements at level organisation, we argue these factors insufficient physically system. Our thesis one fundamental principles multicellularity, which missing or underdeveloped current accounts, functional In view, capability be space plays central role context, enables size, even specialised functions immunity. We extracellular matrix crucial active respect, evolutionary ancient specific (non-cellular) control subsystem contributes specification modulate fate behaviour. also analyse exert upon internal movement communication. Finally, show involved failures aging cancer.

Язык: Английский

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Explaining AI through mechanistic interpretability

European Journal for Philosophy of Science, Год журнала: 2024, Номер 14(4)

Опубликована: Окт. 11, 2024

Abstract Recent work in explainable artificial intelligence (XAI) attempts to render opaque AI systems understandable through a divide-and-conquer strategy. However, this fails illuminate how trained as whole . Precisely kind of functional understanding is needed, though, satisfy important societal desiderata such safety. To remedy situation, we argue, researchers should seek mechanistic interpretability , viz. apply coordinated discovery strategies familiar from the life sciences uncover organisation complex systems. Additionally, theorists accommodate for unique costs and benefits their portrayals XAI research.

Язык: Английский

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Control mechanisms: Explaining the integration and versatility of biological organisms

Adaptive Behavior, Год журнала: 2022, Номер 30(5), С. 389 - 407

Опубликована: Янв. 27, 2022

Living organisms act as integrated wholes to maintain themselves. Individual actions can each be explained by characterizing the mechanisms that perform activity. But these alone do not explain how various activities are coordinated and performed versatilely. We argue this depends on a specific type of mechanism, control mechanism. develop an account examining several extensively studied operative in bacterium E. coli. On our analysis, what distinguishes mechanism from other is it relies measuring one or more variables, which results setting constraints determine its action flexible mechanisms. In most basic arrangement, measurement process directly determines but complex arrangements signals mediate between measurements effectors. This opens possibility multiple responses same based measurements. It also allows crosstalk, resulting networks Such integrate behaviors organism present challenge tailoring particular discuss activity still result differential, versatile, .

Язык: Английский

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Glycemia Regulation: From Feedback Loops to Organizational Closure

Frontiers in Physiology, Год журнала: 2020, Номер 11

Опубликована: Фев. 18, 2020

Endocrinologists apply the idea of feedback loops to explain how hormones regulate certain bodily functions such as glucose metabolism. In particular, focus on maintenance plasma concentrations within a narrow range. Here, we put forward different, organicist perspective endocrine regulation glycaemia, by relying pivotal concept closure constraints. From this perspective, biological systems are understood organized ones, which means that they constituted set mutually dependent functional structures acting constraints, whose depends their reciprocal interactions. Closure refers specifically mutual dependence among constraints in an organism. We show that, when compared loops, organizational can generate much richer descriptions processes and at play metabolism making explicit different hierarchical orders involved. expect proposed theoretical framework will open way construction original mathematical models, would provide better understanding from perspective.

Язык: Английский

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Constraints on Localization and Decomposition as Explanatory Strategies in the Biological Sciences 2.0

Studies in brain and mind, Год журнала: 2020, Номер unknown, С. 363 - 393

Опубликована: Дек. 2, 2020

Язык: Английский

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