Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.

• MeSH
• adenin škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• adenosin škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• adenosinmonofosfát škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• alanin škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• amidy škodlivé účinky   metabolismus   farmakologie   MeSH
• antivirové látky škodlivé účinky   metabolismus   farmakologie   MeSH
• chlorochin škodlivé účinky   analogy a deriváty   metabolismus   farmakologie   MeSH
• COVID-19 metabolismus   MeSH
• dusíkaté sloučeniny škodlivé účinky   metabolismus   farmakologie   MeSH
• farmakoterapie COVID-19 * MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• objevování léků * MeSH
• pyraziny škodlivé účinky   metabolismus   farmakologie   MeSH
• pyrrolidiny škodlivé účinky   metabolismus   farmakologie   MeSH
• racionální návrh léčiv MeSH
• ribavirin škodlivé účinky   metabolismus   farmakologie   MeSH
• SARS-CoV-2 účinky léků   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• thiazoly škodlivé účinky   metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• adenosin MeSH
• adenosinmonofosfát MeSH
• alanin MeSH
• amidy MeSH
• antivirové látky MeSH
• chlorochin MeSH
• dusíkaté sloučeniny MeSH
• favipiravir MeSH Prohlížeč
• galidesivir MeSH Prohlížeč
• nitazoxanide MeSH Prohlížeč
• pyraziny MeSH
• pyrrolidiny MeSH
• remdesivir MeSH Prohlížeč
• ribavirin MeSH
• thiazoly MeSH

Chemical weapons are a major worldwide problem, since they are inexpensive, easy to produce on a large scale and difficult to detect and control. Among the chemical warfare agents, we can highlight the organophosphorus compounds (OP), which contain the phosphorus element and that have a large number of applications. They affect the central nervous system and can lead to death, so there are a lot of works in order to design new effective antidotes for the intoxication caused by them. The standard treatment includes the use of an anticholinergic combined to a central nervous system depressor and an oxime. Oximes are compounds that reactivate Acetylcholinesterase (AChE), a regulatory enzyme responsible for the transmission of nerve impulses, which is one of the molecular targets most vulnerable to neurotoxic agents. Increasingly, enzymatic treatment becomes a promising alternative; therefore, other enzymes have been studied for the OP degradation function, such as phosphotriesterase (PTE) from bacteria, human serum paraoxonase 1 (HssPON1) and diisopropyl fluorophosphatase (DFPase) that showed significant performances in OP detoxification. The understanding of mechanisms by which enzymes act is of extreme importance for the projection of antidotes for warfare agents, and computational chemistry comes to aid and reduce the time and costs of the process. Molecular Docking, Molecular Dynamics and QM/MM (quantum-mechanics/molecular-mechanics) are techniques used to investigate the molecular interactions between ligands and proteins.

• Klíčová slova
• computational methods, enzymatic biodegradation, oximes, warfare nerve agents,
• Publikační typ
• časopisecké články MeSH