TY - JOUR
T1 - Molecular modeling piloted analysis for semicarbazone derivative of curcumin as a potent Abl-kinase inhibitor targeting colon cancer
AU - Rodrigues, Fiona C.
AU - Hari, Gangadhar
AU - Pai, K. S.R.
AU - Suresh, Akhil
AU - Nayak, Usha Y.
AU - Anilkumar, N. V.
AU - Thakur, Goutam
N1 - Funding Information:
The authors wish to thank the Department of Biomedical Engineering, MIT-Manipal for rendering their laboratory facilities. The computational facility is funded by Department of Science and Technology-Science and Engineering Research Board (DST-SERB), New Delhi to Dr. Usha Y. Nayak (EMR/2016/007006).
Funding Information:
Open access funding provided by Manipal Academy of Higher Education, Manipal. One of the authors wishes to acknowledge the Dr. TMA Pai PhD Fellowship and KSTePS, DST, Govt. of Karnataka for the fellowship and continuity of funding. Grant number: ENG-01:2019-20
Funding Information:
The authors wish to thank the Department of Biomedical Engineering, MIT-Manipal for rendering their laboratory facilities. The computational facility is funded by Department of Science and Technology-Science and Engineering Research Board (DST-SERB), New Delhi to Dr. Usha Y. Nayak (EMR/2016/007006).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC50 value of 5.85 µM, which was sevenfold lower as compared to Curcumin’s IC50 of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy.
AB - The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC50 value of 5.85 µM, which was sevenfold lower as compared to Curcumin’s IC50 of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy.
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U2 - 10.1007/s13205-021-03051-9
DO - 10.1007/s13205-021-03051-9
M3 - Article
AN - SCOPUS:85119588206
SN - 2190-572X
VL - 11
JO - 3 Biotech
JF - 3 Biotech
IS - 12
M1 - 506
ER -
