Theophylline: Old Drug in a New Light, Application in COVID-19 through Computational Studies

Abstract

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.

Theophylline-Induced Relaxation Is Enhanced after Testosterone Treatment via Increased KV1.2 and KV1.5 Protein Expression in Guinea Pig Tracheal Smooth Muscle

“…Additionally, some patients who do not develop type 2 airway inflammation exhibit IL-17A-mediated neutrophil inflammation [ 89 ] which is also reduced by nanomolar concentrations of TES [ 40 , 43 , 92 ]. In this regard, theophylline is a well-known anti-inflammatory drug with several proposed action mechanisms [ 2 , 3 , 93 ]. One of these mechanisms is the inhibition of PDEs located in inflammatory cells, which leads to increased cAMP concentration.…”

Theophylline Attenuates BLM-Induced Pulmonary Fibrosis by Inhibiting Th17 Differentiation

“…Theophylline is also prescribed at lower concentrations based on its anti-inflammatory effects in COPD [ 29 , 30 , 31 ]. Recently, theophylline was a possibility in the treatment of COVID-19 patients as it is characterized by bronchodilatory, immunomodulatory, and potentially antiviral mechanisms [ 32 ]. Moreover, other xanthine derivatives, such as doxophylline and theobromine, work as a β2-adrenergic receptor (β 2 -AR) agonist, so they derivate airway smooth muscle relaxation via increasing the cAMP and PKA signaling pathways [ 33 ].…”

Nucleoside‐Based Drug Target with General Antimicrobial Screening and Specific Computational Studies against SARS‐CoV‐2 Main Protease

“…Computational studies have emerged as a powerful tool in this endeavor, offering insights into potential inhibitors that can be further explored experimentally [161,162] . In summary, computational simulation studies significantly expedite the drug discovery process by providing invaluable insights, reducing experimental workloads, and accelerating the identification and development of potential treatments for COVID‐19, leading to a more efficient and effective drug development pipeline [163] …”