Development and Testing of Druglike Screening Libraries

Wang, Junmei; Ge, Yubin; Xie, Xiang‐Qun

doi:10.1021/acs.jcim.8b00537

Cited by 24 publications

(20 citation statements)

References 106 publications

(181 reference statements)

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“…We have conducted a survey on DTIs collected by the DrugBank database 5 and found that on average each drug has 3 drug targets and each drug target has 4.7 drugs. 6 The analysis demonstrates that polypharmacology is a common phenomenon. It is important to identify potential DTIs for both approved drugs and drug candidates, which serves as the basis of repurposing drugs and selection of drug targets without DTIs that may cause side-effects.…”

Section: Introductionmentioning

confidence: 99%

Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study

Wang

2020

Preprint

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127

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The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved. Taking the advantage of a recently released crystal structure of COVID-19 protease in complex with a covalently-bonded inhibitor, N3, 1 I conducted virtual docking screening of approved drugs and drug candidates in clinical trials.For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-PBSA-WSAS. 2-4 Several promising known drugs stand out as potential inhibitors of COVID-19 protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir. Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.82 kcal/mol. Streptomycin, an antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.82 kcal/mol) is not nearly as low as that of the neutral form (-7.92 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.86 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hotspot residue HIS41, is a conserved residue across many viruses including COVID-19, SARS, MERS, and HCV. The findings of this study can facilitate rational drug design targeting the COVID-19 protease.

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Section: Introductionmentioning

confidence: 99%

Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study

Wang

2020

Preprint

Self Cite

127

169

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“…While it might seem intuitive that the greater the number of compounds screened, the greater the chances of finding success, lessons learned from the screening of large libraries suggest that the quality of a compound library, is an equally critical factor in identifying quality hit compounds. [20] These factors include appropriately diverse and/or complex scaffolds which allow for a broad and efficient exploration of chemical space. [21][22][23][24] In addition, libraries should be carefully curated to limit the presence of toxicophores and the influence of frequent hitters (PAINS), in a process referred to as negative design.…”

Section: Screeningmentioning

confidence: 99%

Into the Fray! A Beginner's Guide to Medicinal Chemistry

Veale

2021

ChemMedChem

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Modern medicinal chemistry is a complex, multidimensional discipline that operates at the interface of the chemical and biological sciences. The medicinal chemistry contribution to drug discovery is typically described in the context of the wellrecited linear progression of the drug discovery pipeline. However, compound optimization is idiosyncratic to each project, and clear definitions of hit and lead molecules and the subsequent progress along the pipeline becomes easily blurred. In addition, this description lacks insight into the entangled relationship between chemical and pharmacological properties, and thus provides limited guidance on how innovative medicinal chemistry strategies can be applied to solve optimization problems, regardless of the stage in the pipeline. Through discussion and illustrative examples, this article seeks to provide insights into the finesse of medicinal chemistry and the subtlety of balancing chemical properties pharmacology. In so doing, it aims to serve as an accessible and simple-to-digest guide for anyone who wishes to learn about the underlying principles of medicinal chemistry, in a context that has been decoupled from the pipeline description.

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“…SI 3b) and the asymptotic significance (two-tailed) by Mann-Whitney test was less than 0.01, indicating that active compounds tend to have better docking scores than randomly selected ones. The calculated enrichment factor, 5.7, is a typical value for a GPCR receptor that has crystal structure [61].…”

Section: Model Validation With Enrichment Testmentioning

confidence: 99%

Significantly different effects of tetrahydroberberrubine enantiomers on dopamine D1/D2 receptors revealed by experimental study and integrated in silico simulation

Bian

et al. 2019

J Comput Aided Mol Des

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Tetrahydroberberrubine (TU), an active tetrahydroprotoberberines (THPBs), is gaining increasing popularity as a potential candidate for treatment of anxiety and depression. One of its two enantiomers, l-TU, has been reported to be an antagonist of both D1 and D2 receptors, but the functional activity of the other enantiomer, d-TU, is still unknown. In this study, experiments were combined with in silico molecular simulations to (1) confirm and discover the functional activities of l-TU and d-TU, and (2) systematically evaluate the molecular mechanisms beyond the experimental observations. l-TU proved to be an antagonist of both D1 and D2 receptors (IC 50 = 385 nM and 985 nM, respectively), while d-TU shows no affinity against either D1 or D2 receptor, based on the cAMP assay (D1 receptor) and calcium flux assay (D2 receptor). Results from both flexible-ligand docking studies and molecular dynamic (MD) simulations provided insights at the atomic level. The l-TU-bound structures predicted by MD (1) undergo an outward rotation of the extracellular helical bundles; (2) have an enlarged orthosteric binding pocket; and (3) have a central toggle switch that is prevented from rotating freely. These features are unique to the l-TU enantiomer and provide an explanation for its antagonistic behavior toward both D1 and D2 receptors. The present study provides new sight on the structural and functional relationships of l-TU and d-TU binding to dopamine receptors, and provides guidance to the rational design of novel molecules targeting these two dopamine receptors in the future.

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Development and Testing of Druglike Screening Libraries

Cited by 24 publications

References 106 publications

Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study

Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study

Into the Fray! A Beginner's Guide to Medicinal Chemistry

Significantly different effects of tetrahydroberberrubine enantiomers on dopamine D1/D2 receptors revealed by experimental study and integrated in silico simulation

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