Discovery of potential Aurora-A kinase inhibitors by 3D QSAR pharmacophore modeling, virtual screening, docking, and MD simulation studies

M, Gurubasavaraja Swamy P; Abbas, Nahid; Dhiwar, Prasad Sanjay; Singh, Ekta; Ghara, Abhishek; Das, Arka

doi:10.1080/07391102.2021.2004236

Cited by 9 publications

(4 citation statements)

References 64 publications

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“…This scenario was also seen in almost all the active ligands and, therefore, these interactions helped to stabilize the active ligands in their binding to the RBD, thus orientating the ligands with hydrophobic features towards the hydrophobic pocket of the receptor. This has been previously reported to be crucial for Aurora A kinase inhibitory activity [ 38 – 40 ]. For Leu139, this residue interacts with the amide functional group of the most active ligand 6a, while Ala213 is seen to interact with the central isatin core of all the active Aurora A kinase inhibitors (Fig.…”

Section: Resultsmentioning

confidence: 89%

“…4 ), it was shown that they both interact with Leu139 and Ala213. It has been proven that the Aurora A kinase domain consists of a hydrophobic pocket composed of Leu263, Gly216, and Leu139 [ 38 ]. Besides this, the amino acid duo Ala213 and Arg137 is known to assist in anchoring the ligand to direct them in the abovementioned hydrophobic pocket through bidentate hydrogen bond formation.…”

Section: Resultsmentioning

confidence: 99%

“…Meanwhile, it was observed that active compounds 6a, 6b, 6c, 6f, 6g , and 6i all make interactions with both Lys162 and Glu211, indicating that Lys162 and Glu211 could be important for activity. It must be noted that, since Lys is hydrophilic, interactions with the hydrophobic portions of the ligands with hydrophobic residues would bring about increased activity [38–41] . Most importantly, in this work, ligand 6a was seen to have an interaction with Thr217 which, from previous studies, has been proven to account for selectivity towards Aurora A kinase.…”

Section: Resultsmentioning

confidence: 99%

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Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Eni,

Cassel,

Namba-Nzanguim

et al. 2024

Med Chem Res

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Isatin (indol-2,3-dione), a secondary metabolite of tryptophan, has been used as the core structure to design several compounds that have been tested and identified as potent inhibitors of apoptosis, potential antitumor agents, anticonvulsants, and antiviral agents. In this work, several analogs of isatin hybrids have been synthesized and characterized, and their activities were established as inhibitors of both Aurora A kinase and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike/host angiotensin-converting enzyme II (ACE2) interactions. Amongst the synthesized isatin hybrids, compounds 6a, 6f, 6g, and 6m exhibited Aurora A kinase inhibitory activities (with IC50 values < 5 $$\mu$$ μ M), with GScore values of −7.9, −7.6, −8.2 and −7.7 kcal/mol, respectively. Compounds 6g and 6i showed activities in blocking SARS-CoV-2 spike/ACE2 binding (with IC50 values in the range < 30 $$\mu$$ μ M), with GScore values of −6.4 and −6.6 kcal/mol, respectively. Compounds 6f, 6g, and 6i were both capable of inhibiting spike/ACE2 binding and blocking Aurora A kinase. Pharmacophore profiling indicated that compound 6g tightly fits Aurora A kinase and SARS-CoV-2 pharmacophores, while 6d fits SARS-CoV-2 and 6l fits Aurora A kinase pharmacophore. This work is a proof of concept that some existing cancer drugs may possess antiviral properties. Molecular modeling showed that the active compound for each protein adopted different binding modes, hence interacting with a different set of amino acid residues in the binding site. The weaker activities against spike/ACE2 could be explained by the small sizes of the ligands that fail to address the important interactions for binding to the ACE2 receptor site.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Eni,

Cassel,

Namba-Nzanguim

et al. 2024

Med Chem Res

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“…All water molecules were deleted using MOE software [51]. Further preparation of the protein structures preparation was done using the Protein Preparation Wizard of Schrödinger software [55] (S. Release, 2017-2). Here, bond orders were assigned and hydrogen atoms added, missing side chains were lled using PRIME implemented in the Maestro package, while the Hbond network was subsequently optimised.…”

Section: Preparationmentioning

confidence: 99%

Design, synthesis, and biological and computational evaluation of novel oxindole derivatives as inhibitors of Aurora A Kinase and SARS-CoV-2 Spike/Host ACE2 Interaction

Eni,

Cassel,

Namba-Nzanguim

et al. 2024

Preprint

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Isatin (indol-2,3-dione), a secondary metabolite of tryptophan has been used as the core structure in the designation of several compounds that have been tested and identified as potent inhibitors of apoptosis, potential antitumor agents, anticonvulsants, and antiviral agents. In this work, several analogues of isatin hybrids have been synthesized and characterized, and their inhibitory activities established as inhibitors of both Aurora A kinase and SARS-CoV-2 spike/host ACE2 interactions. Amongst the synthesized isatin hybrids, compounds 6a – 6d, and 6m exhibited interesting Aurora A kinase inhibitory activity while compounds 6h and 6l showed interesting activity in blocking SARS-CoV-2 spike with the ACE2 protein. Compounds 6f, 6g, and 6i possessed both inhibitory activities. Pharmacophore profiling indicated that compound 6g, tightly fits Aurora A kinase and SARS-CoV-2 pharmacophore while 6d fits SARS-CoV-2 and 6l Aurora A kinase. This work is a proof of concept that most existing cancer drugs possess antiviral properties. Molecular modeling showed that the active compound for each protein adopted different binding modes, hence interacting with a different set of amino acid residues in the binding site. For the Aurora A kinase inhibitors, it was shown that the important residues for binding were Leu139, Ala213, Lys162 and Glu211. The weaker activities against spike/ACE2 could be explained by the small sizes of the ligands that fail to address the important interactions for binding to the angiotensin II receptor site.

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Nature-Based Computing Bioinformatics Approaches in Drug Discovery Against Promising Molecular Targets Carbonic Anhydrases and Serine/Threonine Kinases for Cancer Treatment

Peerzada¹,

Rizvi²,

KK³

et al. 2022

Nature-Inspired Intelligent Computing Techniques in Bioinformatics

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Discovery of potential Aurora-A kinase inhibitors by 3D QSAR pharmacophore modeling, virtual screening, docking, and MD simulation studies

Cited by 9 publications

References 64 publications

Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Design, synthesis, and biological and computational evaluation of novel oxindole derivatives as inhibitors of Aurora A Kinase and SARS-CoV-2 Spike/Host ACE2 Interaction

Nature-Based Computing Bioinformatics Approaches in Drug Discovery Against Promising Molecular Targets Carbonic Anhydrases and Serine/Threonine Kinases for Cancer Treatment

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