COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now–New Hopes?

Eynde, Jean Jacques Vanden

doi:10.3390/ph14070664

Cited by 5 publications

(6 citation statements)

References 108 publications

(106 reference statements)

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“…In the recent studies and reviews, a lot of concerns have been raised on the ineffectiveness of the repurposing of drugs [62][63][64][65], which can also be due to mutations [66] in target proteins. This has led to the search for new active sites on receptors.…”

Section: Discussionmentioning

confidence: 99%

De Novo Design of Anti-COVID Drugs Using Machine Learning-Based Equivariant Diffusion Model Targeting the Spike Protein

Niranjan,

Uttarkar,

Ramakrishnan

et al. 2023

CIMB

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The drug discovery and research for an anti-COVID-19 drug has been ongoing despite repurposed drugs in the market. Over time, these drugs were discontinued due to side effects. The search for effective drugs is still under process. The role of Machine Learning (ML) is critical in the search for novel drug compounds. In the current work, using the equivariant diffusion model, we built novel compounds targeting the spike protein of SARS-CoV-2. Using the ML models, 196 de novo compounds were generated which had no hits on any major chemical databases. These novel compounds fulfilled all the criteria of ADMET properties to be lead-like and drug-like compounds. Of the 196 compounds, 15 were docked with high confidence in the target. These compounds were further subjected to molecular docking, the best compound having an IUPAC name of (4aS,4bR,8aS,8bS)-4a,8a-dimethylbiphenylene-1,4,5,8(4aH,4bH,8aH,8bH)-tetraone and a binding score of −6.930 kcal/mol. The principal compound is labeled as CoECG-M1. Density Function Theory (DFT) and Quantum optimization was carried out along with the study of ADMET properties. This suggests that the compound has potential drug-like properties. The docked complex was further subjected to MD simulations, GBSA, and metadynamics simulations to gain insights into the stability of binding. The model can be in the future modified to improve the positive docking rate.

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Section: Discussionmentioning

confidence: 99%

De Novo Design of Anti-COVID Drugs Using Machine Learning-Based Equivariant Diffusion Model Targeting the Spike Protein

Niranjan,

Uttarkar,

Ramakrishnan

et al. 2023

CIMB

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“…3.1.1. Preparation of Methyl 2-Cyclohexyl-2-Hydroxy-2-Phenylacetate (8) and the Corresponding Acid (9) There are two routes (Scheme 1) to obtain reagents 8 and 9. One route starts from 2- paper, the knowledge acquired on the syntheses, mode of action, metabolism, and formulations of this substance.…”

Section: Syntheses Of the Racemic Mixturementioning

confidence: 99%

“…3.1.1. Preparation of Methyl 2-Cyclohexyl-2-Hydroxy-2-Phenylacetate (8) and the Corresponding Acid (9) There are two routes (Scheme 1) to obtain reagents 8 and 9. One route starts from 2-oxo-2-phenylacetic acid (phenylglyoxylic acid; 5), which is first converted into the acid chloride 6 by treatment with thionyl chloride.…”

Section: Syntheses Of the Racemic Mixturementioning

confidence: 99%

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Repositioning Oxybutynin Hydrochloride: State of the Art in Synthesis, Mode of Action, Metabolism, and Formulations

Vanden Eynde

2023

DDC

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For decades, oxybutynin hydrochloride has been prescribed to improve bladder control in cases of incontinence and excessive urination frequency. This review summarizes synthetic methods enabling the preparation of the racemic drug and, in a detailed manner, preparation of (S)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid, a key intermediate in the synthesis of (S)-oxybutynin. The mode of action and metabolism are briefly addressed in order to explain the main adverse effects associated with its use and to justify the evolution observed in the diverse commercial formulations. Repositioning opportunities are discussed in terms of clinical trials for the management of hyperhidrosis, hot flashes, and obstructive sleep apnea.

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“…The hope for the rapid discovery of an effective drug therapy has led to several efforts to repurpose drugs approved for other indications to treat the viral pneumonia [1]. For instance, as of May 2021, 276 clinical trials of the anti-malarial drug hydroxychloroquine had been initiated [2]. Along this line, many drugs that have been identified in vitro as inhibitors of SARS-CoV-2 replication are false positive that fall into a category of agents that induce phospholipidosis in cultured cells [3].…”

Section: Introductionmentioning

confidence: 99%

Failed Repurposing of Lysosomotropic Drugs for COVID-19 Treatment or Prevention

Marceau

2022

DDC

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The hope for the rapid discovery of an effective drug therapy for COVID-19 has led to several efforts to repurpose drugs approved for other indications. Lysosomotropic drugs, organic amines such as chloroquine, hydroxychloroquine, amiodarone and many others, were found to interfere with the viral life cycle in vitro but have failed in clinical trials. The properties of lysosomotropic drugs and the vacuolar cytopathology induced by them are briefly reviewed, including the critical role of lipophilicity, the central role of vacuolar (V)-ATPase for their concentration in acidic organelles, the altered function of these organelles including impaired endocytosis and secretion, macroautophagic accumulation and secondary phospholipidosis. The apparent preferential uptake of lysosomotropic drugs by phagocytic leukocytes (macrophages, neutrophils) and the high concentrations needed for a sustained disruption of vacuolar trafficking may have contributed to the failure of lysosomotropic drug repurposing for COVID-19.

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COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now–New Hopes?

Cited by 5 publications

References 108 publications

De Novo Design of Anti-COVID Drugs Using Machine Learning-Based Equivariant Diffusion Model Targeting the Spike Protein

De Novo Design of Anti-COVID Drugs Using Machine Learning-Based Equivariant Diffusion Model Targeting the Spike Protein

Repositioning Oxybutynin Hydrochloride: State of the Art in Synthesis, Mode of Action, Metabolism, and Formulations

Failed Repurposing of Lysosomotropic Drugs for COVID-19 Treatment or Prevention

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