Identification of Novel IGF1R Kinase Inhibitors by Molecular Modeling and High-Throughput Screening

Moriev, Roman; Vasylchenko, O. V.; Платонов, М. О.; Grygorenko, Oleksandr O.; Volkova, K.; Zozulya, Sergey

doi:10.32607/20758251-2013-5-2-90-99

Cited by 5 publications

(3 citation statements)

References 23 publications

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“…First of all, the crystal structure of IGF-1R has been determined (73). Based on this structural information, the interactions between IGF-1R and small-molecule inhibitors are well defined, and extensive in silico molecular docking analyses have been carried out (74)(75)(76). Combining what is known about the well-defined interaction mechanism between small molecules and IGF-1R with our data pertinent to the penetration of PQ401 into Gram-positive bacterial lipid bilayers, it seems likely that it would be possible to eliminate the IGF-1R-inhibitory activity of PQ401 without the loss of its bacterial membrane-disrupting activity.…”

Section: Discussionmentioning

confidence: 99%

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

Kim

Zou

Pan

et al. 2020

mBio

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Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. IMPORTANCE Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus. PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.

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Section: Discussionmentioning

confidence: 99%

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

Kim

Zou

Pan

et al. 2020

mBio

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“…In contrast to SHS, no previous study has reported antiviral activity for I-OMe-AG538, which was originally characterised as an insulin growth factor 1 receptor protein tyrosine kinase inhibitor [ 35 , 36 ]. This study establishes I-OMe-AG538’s credentials against the flaviviruses DENV, ZIKV and WNV for the first time, revealing it to be an interesting prospect for future development.…”

Section: Discussionmentioning

confidence: 99%

High Throughput Screening Targeting the Dengue NS3-NS5 Interface Identifies Antivirals against Dengue, Zika and West Nile Viruses

Yang

Maher

Wang

et al. 2022

Cells

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Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective therapeutic currently available and controversy surrounding the one approved vaccine. A key factor in dengue viral replication is the interaction between DENV nonstructural proteins (NS) 5 and 3 (NS3) in the infected cell. Here, we perform a proof-of-principle high-throughput screen to identify compounds targeting the NS5-NS3 binding interface. We use a range of approaches to show for the first time that two small molecules–repurposed drugs I-OMe tyrphostin AG538 (I-OMe-AG238) and suramin hexasodium (SHS)–inhibit NS5-NS3 binding at low μM concentration through direct binding to NS5 that impacts thermostability. Importantly, both have strong antiviral activity at low μM concentrations against not only DENV-2, but also Zika virus (ZIKV) and West Nile virus (WNV). This work highlights the NS5-NS3 binding interface as a viable target for the development of anti-flaviviral therapeutics.

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“…For 25 years, we have been participating in the Escape of virtual space by introducing approaches to the compounds widely exploited in HTS, − sulfonamides, ureas, secondary amines, , to name a few. The key point of our research has been to deliver a simple, cost-effective, and highly feasible parallel chemistry.…”

mentioning

confidence: 99%

Expanding Synthesizable Space of Disubstituted 1,2,4-Oxadiazoles

et al. 2016

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One-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from carboxylic acids and nitriles was optimized to parallel chemistry. The method was validated on a 141 member library; the desired products were recovered with a high success rate and in moderate yields. Practical application of the approach was demonstrated in the synthesis of bioactive compound pifexole and agonists of free fatty acid receptor 1. A library of 4 948 100 synthesizable drug-like 3,5-disubstituted 1,2,4-oxadiazoles was enumerated based on the method and available validated reagents.

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Identification of Novel IGF1R Kinase Inhibitors by Molecular Modeling and High-Throughput Screening

Cited by 5 publications

References 23 publications

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

High Throughput Screening Targeting the Dengue NS3-NS5 Interface Identifies Antivirals against Dengue, Zika and West Nile Viruses

Expanding Synthesizable Space of Disubstituted 1,2,4-Oxadiazoles

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