Estimation of Maximum Recommended Therapeutic Dose Using Predicted Promiscuity and Potency

Liu, T; Oprea, Tudor I.; Ursu, Oleg; Hasselgren, Catrin; Altman, Russ B.

doi:10.1111/cts.12422

Cited by 12 publications

(10 citation statements)

References 19 publications

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“…It was also reported that low MRTD drugs often have high pseudo-potency (Liu et al, 2016). On the other hand, drugs of low pseudo-potency need high dose to reach the desired therapeutic effects (Liu et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…These predicted MRTD dose can be instrumental to estimate the starting dose in phase I clinical trials, reducing the number of animals used in preliminary toxicology studies (Schymanet al, 2017). It was also reported that low MRTD drugs often have high pseudo-potency (Liu et al, 2016). On the other hand, drugs of low pseudo-potency need high dose to reach the desired therapeutic effects (Liu et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

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Nature to Nurture- Identifying Phytochemicals from Indian Medicinal Plants as Prophylactic Medicine by Rational Screening to Be Potent Against Multiple Drug Targets of SARS-CoV-2

PrataKumar¹

2020

Preprint

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The COVID-19 pandemic resulted in millions of people being quarantined, impacting the world economy and health sector. There is no existing proven treatment for this disease. It may takea long time until a good candidate vaccine or a potent drug is made available in the market. Therefore, there is a need to search for alternative therapy. In the context, this work explored natural compounds from Indian medicinal plants to develop a prophylactic treatment regimen that will be instrumentalin controlling the spread of the deadly virus. In this work 1916 phytochemicals from 55 Indian medicinal plants, reported to possess anti-viral properties, were subjected to virtual screening on 8 structural and non-structural SARS-CoV-2 protein targets. Docking interactions, ADME and toxicity profiles of the 66 screened phytochemicals were correlated with 21 repurposed drugs that have been most cited in literature to be effective against SARS-CoV-2. Steroidal lactones from Withaniasomnifera and triterpenoids from Azadirachtaindica- with docking score ranging from -13 kcal/mol upto -6 kcal/mol were identified to occupy the top scoring virtually screened phytochemicals against the various targets of SARS-CoV-2. Importantly this work proposes that a concoction of these phytochemicals can act as prophylactic anti-viral medicine to control the spread of SARS-CoV-2 and also enhance natural immunity as the first line of defence towards such a deadly virus.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Nature to Nurture- Identifying Phytochemicals from Indian Medicinal Plants as Prophylactic Medicine by Rational Screening to Be Potent Against Multiple Drug Targets of SARS-CoV-2

PrataKumar¹

2020

Preprint

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“…(Ferreira & Andricopulo, 2019) Category 0 indicates FDAMDD negative while category 1 indicates FDAMDD positive nature. (Liu, Oprea, Ursu, Hasselgren, & Altman, 2016) The highest FDAMDD value was found for nos88 while the lowest value is found for nos37.…”

Section: Toxicity Properties Of Top-six Noscapinesmentioning

confidence: 87%

Inhibition of Protease of Novel Corona Virus by Designed Noscapines: Molecular Docking and ADMET Studies

Vishvakarma¹,

Kumari²,

Singh

2020

Preprint

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<p>Nowadays, many people were dying due to infectious coronavirus diseases (COVID-19). It belongs to the betacoronavirus family and also known as SARS-CoV-2. However, COVID-19 is a new form that has some basic difference in the genome which makes it more lethal and infectious. In transmitted in human in late December 2019 and it infected about 20 million till date. Its genome is composed of positive-sense single-stranded RNA, which encodes for the poly-protein. This poly-protein further cleaved into various components of the virus to make the numerous copy of the virus. There are many more similarities in their genome among the SARS-CoV-2, SARS-CoV, MERS-CoV. However, protease proteins are responsible for the cleavage and hence, COVID-19 main protease is a prime therapeutic target. To date, no medicine/ vaccine can fully cure their infection. To inhibit the activity of protease of COVID-19, molecular docking and ADMET studies of 116 noscapine derivatives were performed and the result was compared with 14 reputed antiviral drugs including chloroquine and hydroxychloroquine. The molecular docking result indicates a better binding in comparison of 14 reputed drugs. Further, the top six noscapines was taken into consideration for the pose analysis and ADMET studies. Finally, the top six noscapine was refined by ADMET properties to get the most potent one.</p>

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“…The Drug-binding Dataset collects 984 high-quality 3D structures (x-ray resolution higher than 2.5 Å) that co-crystalized with FDA approved small molecule drugs (non-nutraceuticals), representing binding environments of 284 distinct drugs [50]. The Human Off-target Dataset comprises 2271 proteins representing a non-redundant representative set (90% percent identity) of human proteins and their close homologs that have high quality 3D structures (x-ray resolution higher than 2.5 Å) in PDB[51]. We have applied PocketFEATURE[46] to predict the probability of binding between the 284 drugs and the 2271 potential off-targets.…”

Section: Methodsmentioning

confidence: 99%

PathFX provides mechanistic insights into drug efficacy and safety for regulatory review and therapeutic development

et al. 2018

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Failure to demonstrate efficacy and safety issues are important reasons that drugs do not reach the market. An incomplete understanding of how drugs exert their effects hinders regulatory and pharmaceutical industry projections of a drug’s benefits and risks. Signaling pathways mediate drug response and while many signaling molecules have been characterized for their contribution to disease or their role in drug side effects, our knowledge of these pathways is incomplete. To better understand all signaling molecules involved in drug response and the phenotype associations of these molecules, we created a novel method, PathFX, a non-commercial entity, to identify these pathways and drug-related phenotypes. We benchmarked PathFX by identifying drugs’ marketed disease indications and reported a sensitivity of 41%, a 2.7-fold improvement over similar approaches. We then used PathFX to strengthen signals for drug-adverse event pairs occurring in the FDA Adverse Event Reporting System (FAERS) and also identified opportunities for drug repurposing for new diseases based on interaction paths that associated a marketed drug to that disease. By discovering molecular interaction pathways, PathFX improved our understanding of drug associations to safety and efficacy phenotypes. The algorithm may provide a new means to improve regulatory and therapeutic development decisions.

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Estimation of Maximum Recommended Therapeutic Dose Using Predicted Promiscuity and Potency

Cited by 12 publications

References 19 publications

Nature to Nurture- Identifying Phytochemicals from Indian Medicinal Plants as Prophylactic Medicine by Rational Screening to Be Potent Against Multiple Drug Targets of SARS-CoV-2

Nature to Nurture- Identifying Phytochemicals from Indian Medicinal Plants as Prophylactic Medicine by Rational Screening to Be Potent Against Multiple Drug Targets of SARS-CoV-2

Inhibition of Protease of Novel Corona Virus by Designed Noscapines: Molecular Docking and ADMET Studies

PathFX provides mechanistic insights into drug efficacy and safety for regulatory review and therapeutic development

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