Abstract:A new and more aggressive strain of coronavirus, known as SARS-CoV-2, which is highly contagious, has rapidly spread across the planet within a short period of time. Due to its high transmission rate and the significant time–space between infection and manifestation of symptoms, the WHO recently declared this a pandemic. Because of the exponentially growing number of new cases of both infections and deaths, development of new therapeutic options to help fight this pandemic is urgently needed. The target molecu… Show more
“…Thus, they can be used as potential noncovalent inhibitors of 3CL pro of SARS-CoV-2. 13 − 16 Some of the most prominent nitrogen-containing heterocycles are the purine scaffolds, which have attracted medicinal interest due to their applications as drug candidates in cancer treatment and viral disorders. 17 , 18 Also, there is a considerable tendency to study new heterocyclic fused imidazopyridine derivatives containing abundant biological activities, such as anticancer, 19 , 20 antiprotozoal agent, 21 antiviral, 22 anti-inflammatory, 23 and anti-Alzheimer’s disease 24 activities.…”
A series of tricyclic and polycyclic pyrido[1,2-
e
]purine derivatives
were designed and synthesized via a two-step, one-pot reaction of
2,4-dichloro-5-amino-6-methylpyrimidine with pyridine under reflux conditions. Various
derivatives of pyrido[1,2-
e
]purine were also synthesized by
substituting the chlorine atom with secondary amines. After careful physiochemical and
pharmacokinetic predictions, the inhibitory effects of the synthesized compounds against
the main protease of SARS-CoV-2 have been evaluated by molecular docking and molecular
dynamics approaches. The in silico results revealed that among all of the studied
compounds, the morpholine/piperidine-substituted pyrido[1,2-
e
]purine
derivatives are the best candidates as effective inhibitors of SARS-CoV-2.
“…Thus, they can be used as potential noncovalent inhibitors of 3CL pro of SARS-CoV-2. 13 − 16 Some of the most prominent nitrogen-containing heterocycles are the purine scaffolds, which have attracted medicinal interest due to their applications as drug candidates in cancer treatment and viral disorders. 17 , 18 Also, there is a considerable tendency to study new heterocyclic fused imidazopyridine derivatives containing abundant biological activities, such as anticancer, 19 , 20 antiprotozoal agent, 21 antiviral, 22 anti-inflammatory, 23 and anti-Alzheimer’s disease 24 activities.…”
A series of tricyclic and polycyclic pyrido[1,2-
e
]purine derivatives
were designed and synthesized via a two-step, one-pot reaction of
2,4-dichloro-5-amino-6-methylpyrimidine with pyridine under reflux conditions. Various
derivatives of pyrido[1,2-
e
]purine were also synthesized by
substituting the chlorine atom with secondary amines. After careful physiochemical and
pharmacokinetic predictions, the inhibitory effects of the synthesized compounds against
the main protease of SARS-CoV-2 have been evaluated by molecular docking and molecular
dynamics approaches. The in silico results revealed that among all of the studied
compounds, the morpholine/piperidine-substituted pyrido[1,2-
e
]purine
derivatives are the best candidates as effective inhibitors of SARS-CoV-2.
“…In order to assess the ability of the algorithm to predict likely ligand orientations, in particular, re-docking calculations were then performed in this study using the MolAr software 23 , with the implementation of the AutoDock Vina program 22 . As a result, it is important to note that the values extracted from RMSD (5R82 = 0.94 Ǻ/3H5Y = 1.55 Ǻ) showed that the program used in this study is adequate for predicting the conformation that the co-crystallized ligands adopted experimentally within the viral M pro and RdRp of SARS-CoV-2 12 , 13 , 25 . The re-docking configurations were maintained to perform the docking calculations of the drugs investigated as well as their metabolism fragments.…”
Section: Resultsmentioning
confidence: 83%
“…Thereby, the acute toxicity and other relevant pharmacokinetics parameters can easily be obtained from a rat model-based admetSAR predictor ( http://biosig.unimelb.edu.au/pkcsm/prediction ). This ADMET procedure has been used previously in similar systems with large success 12 , 13 , 25 . Figure 1 Schematic representation of computational strategy proposed in this study to the investigation of the metabolism effect in drug design.…”
Section: Computational Models and Methodsmentioning
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.
“…Recently, enormous efforts have widely focused on facing a new coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a disease designated as COVID-19 [1]. The World Health Organization (WHO) declared the COVID-19 outbreak as a new pandemic on 11 March 2020 [2].…”
Section: Introductionmentioning
confidence: 99%
“…The World Health Organization (WHO) declared the COVID-19 outbreak as a new pandemic on 11 March 2020 [2]. In order to contribute to the front line of the fight against this disease, researchers worldwide are moving to an investigation of an effective treatment regimen (based mainly on known drugs) against infection caused by the SARS-CoV-2 virus [1][2][3][4][5]. Most recently, the combination of drugs, for example, (hydroxy)chloroquine with azithromycin (AZ), has been used as a strategy and has also been clinically tested to treat the SARS-CoV-2 outbreak [6][7][8][9][10][11].…”
In this in silico study, different pharmaceutical co-crystals based on (hydroxy)chloroquine with macrolide antibiotics (azithromycin, clarithromycin, or erythromycin A) were analyzed for the first time. These findings present a new molecular perspective and therefore suggest that the combination of (hydroxy)chloroquine/azithromycin, in the stoichiometric ratio of 1:1, as model co-crystal systems has less toxicity and is the most effective for inhibiting the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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