Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanism
Mitotic kinesins are eukaryotic proteins that play a vital role in cellular mitosis. Their over-expression in malignant rather than normal cells and their specific cellular role made kinesin inhibitors a promising cancer therapeutics. The realization of in-vitro antitumor activity of the investigati...
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Elsevier
2024-06-01
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Series: | Chemical Physics Impact |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2667022424000240 |
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author | Musab Ali Ali H. Rabbad Mahmoud E. Soliman |
author_facet | Musab Ali Ali H. Rabbad Mahmoud E. Soliman |
author_sort | Musab Ali |
collection | DOAJ |
description | Mitotic kinesins are eukaryotic proteins that play a vital role in cellular mitosis. Their over-expression in malignant rather than normal cells and their specific cellular role made kinesin inhibitors a promising cancer therapeutics. The realization of in-vitro antitumor activity of the investigational molecule-monastrol-was traced to its allosteric inhibition of the ATPase activity of the motor domain of Human Kensin-5 (Eg5) and prompted extensive efforts towards kinesin inhibitors. Many reports pointed to the prospect of Kinesin-like protein (KIFC1) as a novel anticancer target. Nevertheless, no verified KIFC1-inhibitor crystallized structure has been reported so far, confirming the scarcity of molecular studies devoted to deciphering claimed potentiality. The significant structural resemblance across the kinesins superfamily sparked our interest in investigating monastrol as a KIFC1 inhibitor.Time-scale findings of molecular dynamics simulation and molecular mechanics/generalized-born surface area (MM/GBSA) methods revealed that monastrol binds with high affinity to an allosteric pocket, inducing notable dynamical alterations evidenced by increased structural stability, rigidity, compactness, and overall folding tendency of KIFC1. Further, these conformational events negatively impacted the affinity of ATP to its site disrupting the essential ATP-KIFC1 dynamics leading to consequential loss of functionality. We concluded that monastrol can act as non-competitive inhibitor of KIFC1 and these findings speculate new anticancer mechanism contributing to the design of highly selective and novel cancer therapeutics. |
first_indexed | 2024-03-08T12:51:11Z |
format | Article |
id | doaj.art-25254fafe29242f7b0c61eee76cdfc17 |
institution | Directory Open Access Journal |
issn | 2667-0224 |
language | English |
last_indexed | 2024-03-08T12:51:11Z |
publishDate | 2024-06-01 |
publisher | Elsevier |
record_format | Article |
series | Chemical Physics Impact |
spelling | doaj.art-25254fafe29242f7b0c61eee76cdfc172024-01-20T04:46:49ZengElsevierChemical Physics Impact2667-02242024-06-018100480Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanismMusab Ali0Ali H. Rabbad1Mahmoud E. Soliman2Molecular Bio-Computation and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001, South AfricaMolecular Bio-Computation and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001, South AfricaCorresponding author.; Molecular Bio-Computation and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001, South AfricaMitotic kinesins are eukaryotic proteins that play a vital role in cellular mitosis. Their over-expression in malignant rather than normal cells and their specific cellular role made kinesin inhibitors a promising cancer therapeutics. The realization of in-vitro antitumor activity of the investigational molecule-monastrol-was traced to its allosteric inhibition of the ATPase activity of the motor domain of Human Kensin-5 (Eg5) and prompted extensive efforts towards kinesin inhibitors. Many reports pointed to the prospect of Kinesin-like protein (KIFC1) as a novel anticancer target. Nevertheless, no verified KIFC1-inhibitor crystallized structure has been reported so far, confirming the scarcity of molecular studies devoted to deciphering claimed potentiality. The significant structural resemblance across the kinesins superfamily sparked our interest in investigating monastrol as a KIFC1 inhibitor.Time-scale findings of molecular dynamics simulation and molecular mechanics/generalized-born surface area (MM/GBSA) methods revealed that monastrol binds with high affinity to an allosteric pocket, inducing notable dynamical alterations evidenced by increased structural stability, rigidity, compactness, and overall folding tendency of KIFC1. Further, these conformational events negatively impacted the affinity of ATP to its site disrupting the essential ATP-KIFC1 dynamics leading to consequential loss of functionality. We concluded that monastrol can act as non-competitive inhibitor of KIFC1 and these findings speculate new anticancer mechanism contributing to the design of highly selective and novel cancer therapeutics.http://www.sciencedirect.com/science/article/pii/S2667022424000240Kinesin inhibitorsKinesin-like proteinMonastrolMolecular dynamic simulationBinding free energyAnticancer agents |
spellingShingle | Musab Ali Ali H. Rabbad Mahmoud E. Soliman Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanism Chemical Physics Impact Kinesin inhibitors Kinesin-like protein Monastrol Molecular dynamic simulation Binding free energy Anticancer agents |
title | Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanism |
title_full | Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanism |
title_fullStr | Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanism |
title_full_unstemmed | Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanism |
title_short | Monastrol disrupts KIFC1-ATP dynamics: Towards newer anticancer mechanism |
title_sort | monastrol disrupts kifc1 atp dynamics towards newer anticancer mechanism |
topic | Kinesin inhibitors Kinesin-like protein Monastrol Molecular dynamic simulation Binding free energy Anticancer agents |
url | http://www.sciencedirect.com/science/article/pii/S2667022424000240 |
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