Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds
The pursuit of small molecule inhibitors targeting hexokinase 2 (HK2) has significantly captivated the field of cancer drug discovery. Nevertheless, the creation of selective inhibitors aimed at specific isoforms of hexokinase (HK) remains a formidable challenge. Here, we present a multiple-pharmaco...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1346270/full |
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| author | Purbali Chakraborty Purbali Chakraborty Syeda Lubna Shouvik Bhuin Deepika K. Manab Chakravarty Trinath Jamma Trinath Jamma Perumal Yogeeswari Perumal Yogeeswari |
| author_facet | Purbali Chakraborty Purbali Chakraborty Syeda Lubna Shouvik Bhuin Deepika K. Manab Chakravarty Trinath Jamma Trinath Jamma Perumal Yogeeswari Perumal Yogeeswari |
| author_sort | Purbali Chakraborty |
| collection | DOAJ |
| description | The pursuit of small molecule inhibitors targeting hexokinase 2 (HK2) has significantly captivated the field of cancer drug discovery. Nevertheless, the creation of selective inhibitors aimed at specific isoforms of hexokinase (HK) remains a formidable challenge. Here, we present a multiple-pharmacophore modeling approach for designing ligands against HK2 with a marked anti-proliferative effect on FaDu and Cal27 oral cancer cell lines. Molecular dynamics (MD) simulations showed that the prototype ligand exhibited a higher affinity towards HK2. Complementing this, we put forth a sustainable synthetic pathway: an environmentally conscious, single-step process facilitated through a direct amidation of the ester with an amine under transition-metal-free conditions with an excellent yield in ambient temperature, followed by a column chromatography avoided separation technique of the identified lead bioactive compound (H2) that exhibited cell cycle arrest and apoptosis. We observed that the inhibition of HK2 led to the loss of mitochondrial membrane potential and increased mitophagy as a potential mechanism of anticancer action. The lead H2 also reduced the growth of spheroids. Collectively, these results indicated the proof-of-concept for the prototypical lead towards HK2 inhibition with anti-cancer potential. |
| first_indexed | 2024-04-25T01:00:35Z |
| format | Article |
| id | doaj.art-794a70d147954a7fa5aa5e05cc2fa07e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-25T01:00:35Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-794a70d147954a7fa5aa5e05cc2fa07e2024-03-11T04:51:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-03-011510.3389/fphar.2024.13462701346270Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compoundsPurbali Chakraborty0Purbali Chakraborty1Syeda Lubna2Shouvik Bhuin3Deepika K.4Manab Chakravarty5Trinath Jamma6Trinath Jamma7Perumal Yogeeswari8Perumal Yogeeswari9Department of Pharmacy, Birla Institute of Technology and Science, Hyderabad, IndiaCancer Research Group, Centre for Human Diseases Research, Birla Institute of Technology and Science, Hyderabad, IndiaDepartment of Biological Sciences, Birla Institute of Technology and Science, Hyderabad, IndiaDepartment of Chemistry, Birla Institute of Technology and Science, Hyderabad, IndiaDepartment of Pharmacy, Birla Institute of Technology and Science, Hyderabad, IndiaDepartment of Chemistry, Birla Institute of Technology and Science, Hyderabad, IndiaCancer Research Group, Centre for Human Diseases Research, Birla Institute of Technology and Science, Hyderabad, IndiaDepartment of Biological Sciences, Birla Institute of Technology and Science, Hyderabad, IndiaDepartment of Pharmacy, Birla Institute of Technology and Science, Hyderabad, IndiaCancer Research Group, Centre for Human Diseases Research, Birla Institute of Technology and Science, Hyderabad, IndiaThe pursuit of small molecule inhibitors targeting hexokinase 2 (HK2) has significantly captivated the field of cancer drug discovery. Nevertheless, the creation of selective inhibitors aimed at specific isoforms of hexokinase (HK) remains a formidable challenge. Here, we present a multiple-pharmacophore modeling approach for designing ligands against HK2 with a marked anti-proliferative effect on FaDu and Cal27 oral cancer cell lines. Molecular dynamics (MD) simulations showed that the prototype ligand exhibited a higher affinity towards HK2. Complementing this, we put forth a sustainable synthetic pathway: an environmentally conscious, single-step process facilitated through a direct amidation of the ester with an amine under transition-metal-free conditions with an excellent yield in ambient temperature, followed by a column chromatography avoided separation technique of the identified lead bioactive compound (H2) that exhibited cell cycle arrest and apoptosis. We observed that the inhibition of HK2 led to the loss of mitochondrial membrane potential and increased mitophagy as a potential mechanism of anticancer action. The lead H2 also reduced the growth of spheroids. Collectively, these results indicated the proof-of-concept for the prototypical lead towards HK2 inhibition with anti-cancer potential.https://www.frontiersin.org/articles/10.3389/fphar.2024.1346270/fulloral cancerhexokinase-2 inhibitorpharmacophoremolecular dynamicsstructure-basedmitochondria membrane potential |
| spellingShingle | Purbali Chakraborty Purbali Chakraborty Syeda Lubna Shouvik Bhuin Deepika K. Manab Chakravarty Trinath Jamma Trinath Jamma Perumal Yogeeswari Perumal Yogeeswari Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds Frontiers in Pharmacology oral cancer hexokinase-2 inhibitor pharmacophore molecular dynamics structure-based mitochondria membrane potential |
| title | Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds |
| title_full | Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds |
| title_fullStr | Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds |
| title_full_unstemmed | Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds |
| title_short | Targeting hexokinase 2 for oral cancer therapy: structure-based design and validation of lead compounds |
| title_sort | targeting hexokinase 2 for oral cancer therapy structure based design and validation of lead compounds |
| topic | oral cancer hexokinase-2 inhibitor pharmacophore molecular dynamics structure-based mitochondria membrane potential |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1346270/full |
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