Identification of small molecule binding pocket for inhibition of Crimean–Congo hemorrhagic fever virus OTU protease

Kocabaş, Fatih; Ergin, Enes K.

doi:10.3906/biy-1501-56

Cited by 5 publications

(7 citation statements)

References 36 publications

(49 reference statements)

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“…The three-dimensional structure of the MEIS homeodomain was downloaded from PDB.org (PDB code: 3K2A) and then processed in the AutodockTools. Briefly, the water molecules were removed, the electrons in the atoms were checked and the crystal structure of the homeodomain was recorded in the form of pdbqt as we have done previously 21,22 . Using AutoDockTools 23 , pockets of conserved residues interacting with TGACAG MEIS binding DNA sequence were highlighted to determine the grid box locations with a 20-20-20°A search space.…”

Section: Molecular Docking and Cardiotoxicity Predictionsmentioning

confidence: 99%

“…Using AutoDockTools 23 , pockets of conserved residues interacting with TGACAG MEIS binding DNA sequence were highlighted to determine the grid box locations with a 20-20-20°A search space. Docking studies were performed using AutoDock Vina 1.1.2 23 and automated using PaDEL-ADV as we have done previously 21,22 . Small molecules library including ZINC drugs-now supset (about 1 million compound), Sigma LOPAC1280 and Homeobox library of inhibitors were docked into MEIS homeodomain.…”

Section: Molecular Docking and Cardiotoxicity Predictionsmentioning

confidence: 99%

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Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Turan

Albayrak

Uslu

et al. 2020

Sci Rep

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Meis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This led us to develop inhibitors of MEIS1 that could modulate HSC activity. To this end, we have established a library of relevant homeobox family inhibitors and developed a high-throughput in silico screening strategy against homeodomain of MEIS proteins using the AutoDock Vina and PaDEL-ADV platform. We have screened over a million druggable small molecules in silico and selected putative MEIS inhibitors (MEISi) with no predicted cytotoxicity or cardiotoxicity. This was followed by in vitro validation of putative MEIS inhibitors using MEIS dependent luciferase reporter assays and analysis in the ex vivo HSC assays. We have shown that small molecules named MEISi-1 and MEISi-2 significantly inhibit MEIS-luciferase reporters in vitro and induce murine (LSKCD34 l°w cells) and human (CD34 + , CD133 + , and ALDH hi cells) HSC self-renewal ex vivo. In addition, inhibition of MEIS proteins results in downregulation of Meis1 and MEIS1 target gene expression including Hif-1α, Hif-2α and HSC quiescence modulators. MEIS inhibitors are effective in vivo as evident by induced HSC content in the murine bone marrow and downregulation of expression of MEIS target genes. These studies warrant identification of first-in-class MEIS inhibitors as potential pharmaceuticals to be utilized in modulation of HSC activity and bone marrow transplantation studies. Meis1 is a member of TALE class of transcription factors 1. Through interaction domains in the N terminus, MEIS1 cooperates in transcription factors PBX1 and HOXA9 to transactivate target genes 2,3. MEIS2 and MEIS3 protein sequences demonstrate a high degree of similarity with MEIS1 4. Meis1 was first described in leukemia mouse model and identified as a viral integration site (reviewed in 5). MEIS proteins are characterized by PBX interaction domains and a highly conserved homeodomain (HD). MEIS1 HD shares identical MEIS2 HD amino acid sequence. Studies to understand how MEIS1 HD interacts with DNA led to crystallization of MEIS1 HD with target DNA and identification of DNA sequence preferentially bound by MEIS proteins as "TGACAG" 6-8. Meis1 is highly expressed in the bone marrow 2,9. Lethality occurs in Meis1 knockout mice at mid gestation (E14.5-15.5) with a number of hematopoietic, vascular and cardiac abnormalities 10-12. Conditional and tissue specific deletion of Meis1 in bone marrow led to loss of HSC quiescence associated with expansion of HSC pool in vivo 13. Meis1 has been shown to regulate HSC metabolism through transcriptional regulation of hypoxia factors including Hif1a and Hif2a 13-16. Deletion of Meis1 or Hif-1α in HSCs leads to reduction in the cytoplasmic glycolysis and induction of mitochondrial phosphorylation. Intriguingly, studies showed a fundamental role of Meis1 in neonatal cardiac regeneration. Increased Me...

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Section: Molecular Docking and Cardiotoxicity Predictionsmentioning

confidence: 99%

Section: Molecular Docking and Cardiotoxicity Predictionsmentioning

confidence: 99%

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Turan

Albayrak

Uslu

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

Section: Molecular Docking and Cardiotoxicity Predictionsmentioning

confidence: 99%

“…Using AutoDockTools 23 , pockets of conserved residues interacting with TGACAG MEIS binding DNA sequence were highlighted to determine the grid box locations with a 20-20-20 o A search space. Docking studies were performed using AutoDock Vina 1.1.2 23 and automated using PaDEL-ADV as we have done previously 21,22 . Small molecules library including ZINC drugs-now supset (about 1 million compound) (Supplementary File 1), Sigma LOPAC1280 and Homeobox library of inhibitors were docked into MEIS homeodomain.…”

Section: Molecular Docking and Cardiotoxicity Predictionsmentioning

confidence: 99%

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Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Turan

Albayrak

Uslu

et al. 2020

Preprint

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AbstractMeis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This led us to develop inhibitors of MEIS1 that could modulate HSC activity. To this end, we have established a library of relevant homeobox family inhibitors and developed a high-throughput in silico screening strategy against homeodomain of MEIS proteins using the AutoDock Vina and PaDEL-ADV platform. We have screened over a million druggable small molecules in silico and selected putative MEIS inhibitors (MEISi) with no predicted cytotoxicity or cardiotoxicity. This was followed by in vitro validation of putative MEIS inhibitors using MEIS dependent luciferase reporter assays and analysis in the ex vivo HSC assays. We have shown that small molecules named MEISi-1 and MEISi-2 significantly inhibit MEIS-luciferase reporters in vitro and induce murine (LSKCD34low cells) and human (CD34+, CD133+, and ALDHhi cells) HSC self-renewal ex vivo. In addition, inhibition of MEIS proteins results in downregulation of Meis1 and MEIS1 target gene expression including Hif-1α, Hif-2α and HSC quiescence modulators. MEIS inhibitors are effective in vivo as evident by induced HSC content in the murine bone marrow and downregulation of expression of MEIS target genes. These studies warrant identification of first-in-class MEIS inhibitors as potential pharmaceuticals to be utilized in modulation of HSC activity and bone marrow transplantation studies.

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Identification of first-in-class plasmodium OTU inhibitors with potent anti-malarial activity

Siyah

Akgöl

Durdağı

et al. 2021

Biochemical Journal

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OTU proteases antagonize the cellular defense in the host cells and involve in pathogenesis. Intriguingly, P. falciparum, P. vivax, and P. yoelii have an uncharacterized and highly conserved viral OTU-like proteins. However, their structure, function or inhibitors have not been previously reported. To this end, we have performed structural modeling, small molecule screening, deconjugation assays to characterize and develop first-in-class inhibitors of P. falciparum, P. vivax, and P. yoelii OTU-like proteins. These Plasmodium OTU-like proteins have highly conserved residues in the catalytic and inhibition pockets similar to viral OTU proteins. Plasmodium OTU proteins demonstrated Ubiquitin and ISG15 deconjugation activities as evident by intracellular ubiquitinated protein content analyzed by western blot and flow cytometry. We screened a library of small molecules to determine plasmodium OTU inhibitors with potent anti-malarial activity. Enrichment and correlation studies identified structurally similar molecules. We have identified two small molecules that inhibit P. falciparum, P. vivax, and P. yoelii OTU proteins (IC50 values as low as 30nM) with potent anti-malarial activity (IC50 of 4.1-6.5 μM). We also established enzyme kinetics, druglikeness, ADME, and QSAR model. MD simulations allowed us to resolve how inhibitors interacted with plasmodium OTU proteins. These findings suggest that targeting malarial OTU-like proteases is a plausible strategy to develop new anti-malarial therapies.

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Identification of small molecule binding pocket for inhibition of Crimean–Congo hemorrhagic fever virus OTU protease

Abstract: IntroductionCrimean-Congo hemorrhagic fever virus (CCHFV) is a deadly tick-borne virus belonging to the family Bunyaviridae, genus Nairovirus. It constitutes a public health threat due to its high mortality rate, up to 6% in hospitalized patients and up to 30%-50% in severe forms

Cited by 5 publications

References 36 publications

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Identification of first-in-class plasmodium OTU inhibitors with potent anti-malarial activity

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