Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation

Durdağı, Serdar; Aksoydan, Busecan; Erol, İsmail; Kantarcioglu, Isik; Ergün, Yavuz; Bulut, Gülay; Acar, Melih; Avşar, Timuçin; Liapakis, George; Karageorgos, Vlasios; Salmas, Ramin Ekhteiari; Sergi, B.; Alkhatib, Sara; Turan, Gizem; Yigit, Berfu Nur; Cantasir, Kutay; Kurt, Bahar; Kılıç, Türker

doi:10.1016/j.ejmech.2017.12.021

Cited by 23 publications

(13 citation statements)

References 57 publications

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“…It is noteworthy that the method known as drug repurposing has become less costly in terms of both time and resources. In our laboratory, the use of molecules in different indications has been investigated with the studies we have done in this field in recent years (Durdagi et al, 2018;Is et al,2018;Tutumlu et al, 2020). Since the most of the preclinic and clinical studies including pharmacokinetic and toxicological studies of approved or compounds in clinical investigation phases have been already tested, they require less time to make them suitable for new indications.…”

Section: Introductionmentioning

confidence: 99%

Virtual drug repurposing study against SARS-CoV-2 TMPRSS2 target

Durdağı¹

2020

Turk J Biol

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Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC's NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.

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Section: Introductionmentioning

confidence: 99%

Virtual drug repurposing study against SARS-CoV-2 TMPRSS2 target

Durdağı¹

2020

Turk J Biol

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“…In addition, we eliminated hits that have high affinity to PBX HD to identify highly specific MEIS inhibitors. Furthermore, we have applied another filter to eliminate any potentially cardiotoxic compounds by determining affinity to hERG channel 24,37 . These findings were further validated by the analysis of Pbx, Tgif1, Tgif2 and pKnox gene expression and their target gene expression profile post MEIS inhibitor treatments.…”

Section: Discussionmentioning

confidence: 99%

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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“…In addition, we eliminated hits that have high affinity to PBX HD to identify highly specific MEIS inhibitors. Furthermore, we have applied another filter to eliminate any potentially cardiotoxic compounds by determining affinity to hERG 22 channel 24,37 . These findings were further validated by the analysis of Pbx, Tgif1, Tgif2 and pKnox gene expression and their target gene expression profile post MEIS inhibitor treatments.…”

Section: Discussionmentioning

confidence: 99%

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.

show abstract

Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation

Cited by 23 publications

References 57 publications

Virtual drug repurposing study against SARS-CoV-2 TMPRSS2 target

Virtual drug repurposing study against SARS-CoV-2 TMPRSS2 target

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

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