Toward an Understanding of Pan-Assay Interference Compounds and Promiscuity: A Structural Perspective on Binding Modes

Bolz, Sarah Naomi; Adasme, Melissa F.; Schroeder, Michael

doi:10.1021/acs.jcim.0c01227

Cited by 31 publications

(13 citation statements)

References 63 publications

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“…All compounds passed both PAINS and Brenk tests as no alerts were raised. This means that these compounds may not affect any bioassays [ 72 ] and generally have good pharmacokinetics properties with an acceptable toxic level [ 73 ]. Interestingly, only one compound ( 6d) passed the lead-likeness test, and hence, can be used as a lead compound in drug discovery processes.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

et al. 2022

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Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3- b ]pyridine derivatives as non-nucleoside A 1 agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound 7c (thieno[2,3- b ]pyridine derivative), displayed good binding affinity to the rA 1 AR ( K i = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3- b ]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives ( 6a - s ) in relation to AR binding was also evaluated. A significant loss of activity against rA 1 /rA 2A ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA 1 ARs ( K i < 10 nM) than rA 2A . Compound 6c had the best rA 1 affinity ( K i = 0.076 nM). Novel compounds ( 6d , 6k , 6l , 6m , 6n , 6o , 6p) were highly selective towards rA 1 AR ( K i between 0.179 and 21.0 nM). Based on their high selectivity for A 1 ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations. A decrease in rA 1 AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3- b ]pyridines ( 7a , 7d , 7c ) from amino-3,5-dicyanopyridine derivatives ( 6a , 6f , 6g ).

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Section: Resultsmentioning

confidence: 99%

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

et al. 2022

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“…Multi-targeting or polypharmacology is not uncommon for natural products, which have been used for thousands of years in traditional medicine [ 38 , 39 ]. In particular, multi-targeting [ 40 ] has advantages over single targeting, e.g. better efficacy, reduced toxicity and, more importantly, the ability to prevent the development of resistant viral strains and to enable the treatment of viral coinfections, e.g.…”

Section: Resultsmentioning

confidence: 99%

Identification and semisynthesis of (−)-anisomelic acid as oral agent against SARS-CoV-2 in mice

Zheng

Yeh

et al. 2022

National Science Review

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(−)-Anisomelic acid (AA), isolated from Anisomeles indica (L.) Kuntze (Labiatae) leaves, is a macrocyclic cembranolide with a trans-fused α-methylene-γ-lactone motif. AA effectively inhibits SARS-CoV-2 replication and viral-induced cytopathic effect (CPE) with an EC50 of 1.1 and 4.3 μM, respectively. Challenge studies of SARS-CoV-2-infected K18-hACE2 mice showed that oral administration of AA and subcutaneous dosing of remdesivir can both reduce the viral titers in the lung tissue at the same level. To facilitate drug discovery, we used a semisynthetic approach to shorten the project timelines. The enantioselective semisynthesis of AA from the naturally enriched and commercially available starting material (+)-costunolide was achieved in five steps with a 27% overall yield. The developed chemistry provides opportunities for developing AA-based novel ligands for selectively targeting proteins involved in viral infections.

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“…PAINS have an unrestrained behavior of producing false positive hits during HTS. Te mechanism is poorly understood; however, it is associated with protein reactivity and noncovalent interactions [38]. In SwissADME a structural alert is created for 105 fragments identifed by Brenk et al which are chemically reactive, toxic, metabolically unstable, or likely to have poor pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, Characterization, and Pharmacokinetic Studies of Thiazolidine-2,4-Dione Derivatives

Ansari

Khan

Jan

et al. 2023

Journal of Chemistry

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Various derivatives of thiazolidine-2,4-dione (C1–C5) were designed and synthesized by chemical reaction with 4-nitrobenzaldehyde using Knoevenagel reaction conditions which results in the reduction of nitro group to amine and further modification results in target compounds. The chemical structures of all the 2,4-thiazolidinedione derivatives have been elucidated by 1H and 13C NMR spectroscopy. These compounds were further characterized by in silico ADME (absorption, distribution, metabolism, and excretion) studies. The pharmacokinetic properties were assessed by SwissADME software. The in silico ADME (absorption, distribution, metabolism, and excretion) assessment reveals that all derivatives (C1 to C5) have 5 to 7 rotatable bonds. Lipophilicity and water solubility showed that C1, C2, and C4 are water soluble except for C3 and C5 which are moderately soluble. All the compounds have high GI absorption except C3. None of the derivatives are blood-brain barrier permeant. Drug metabolism of TZDs derivatives showed that C3 was identified as an inhibitor of CYP2C9 and C5 as an inhibitor of CYP1A2 and CYP2C19. Drug likeness properties indicate that C1 has only one violation of the Ghose rule while C3 has violations in the Ghose and Egan rules. The in silico pharmacokinetic studies revealed high GI absorption and the inability to pass blood-brain barrier which can be further assessed by in vitro and in vivo antihyperglycemic activity. This study will contribute to providing TZDs derivatives with an improved pharmacokinetic profile and decreased toxicity.

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Toward an Understanding of Pan-Assay Interference Compounds and Promiscuity: A Structural Perspective on Binding Modes

Cited by 31 publications

References 63 publications

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

Identification and semisynthesis of (−)-anisomelic acid as oral agent against SARS-CoV-2 in mice

Synthesis, Characterization, and Pharmacokinetic Studies of Thiazolidine-2,4-Dione Derivatives

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