A pipeline for testing drug mechanism of action and combination therapies: From microarray data to simulations via Linear-In-Flux-Expressions: Testing four-drug combinations for tuberculosis treatment.

Computational methods are becoming commonly used in many areas of medical research. Recently, the modeling of biological mechanisms associated with disease pathophysiology have benefited from approaches such as Quantitative Systems Pharmacology (briefly QSP) and Physiologically Based Pharmacokinetics (briefly PBPK). These methodologies show the potential to enhance, if not substitute animal models. The main reasons for this success are the high accuracy and low cost. Solid mathematical foundations of such methods, such as compartmental systems and flux balance analysis, provide a good base on which to build computational tools. However, there are many choices to be made in model design, that will have a large impact on how these methods perform as we scale up the network or perturb the system to uncover the mechanisms of action of new compounds or therapy combinations. A computational pipeline is presented here that starts with available-omic data and utilizes advanced mathematical simulations to inform the modeling of a biochemical system. Specific attention is devoted to creating a modular workflow, including the mathematical rigorous tools to represent complex chemical reactions, and modeling drug action in terms of its impact on multiple pathways. An application to optimizing combination therapy for tuberculosis shows the potential of the approach.

COVID-19 and neurodegeneration: The mitochondrial connection.

There is still a significant lack of knowledge regarding many aspects of the etiopathology and consequences of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans. For example, the variety of molecular mechanisms mediating this infection, and the long-term consequences of the disease remain poorly understood. It first seemed like the SARS-CoV-2 infection primarily caused a serious respiratory syndrome. However, over the last years, an increasing number of studies also pointed towards the damaging effects of this infection has on the central nervous system (CNS). In fact, evidence suggests a possible disruption of the blood-brain barrier and deleterious effects on the CNS, especially in patients who already suffer from other pathologies, such as neurodegenerative disorders. The molecular mechanisms behind these effects on the CNS could involve the dysregulation of mitochondrial physiology, a well-known early marker of neurodegeneration and a hallmark of aging. Moreover, mitochondria are involved in the activation of the inflammatory response, which has also been broadly described in the CNS in COVID-19. Here, we critically review the current bibliography regarding the presence of neurodegenerative symptoms in COVID-19 patients, with a special emphasis on the mitochondrial mechanisms of these disorders.