scholarly journals Anticancer Drug Design: Development of Cyclin-Dependent Kinase Inhibitors Using In Silico Techniques

2020 ◽  
Author(s):  
Derouicha Matmour ◽  
Nawel Achachi ◽  
Yassine Mérad ◽  
Houari Toumi
Keyword(s):  
Cell Cycle ◽  
Drug Design ◽  
Anticancer Drug ◽  
Mammalian Cells ◽  
Drug Candidate ◽  
Biological Databases ◽  
Design Development ◽  
Qsar Study ◽  
Structure Based Drug Design ◽  
Restriction Point

In mammalian cells, proliferation is controlled by the cell cycle, where cyclin-dependent kinases regulate critical checkpoints. CDK4 is considered a highly validated anticancer drug target due to its essential role in regulating cell cycle progression at the G1 restriction point. Our objective is to design novel CDK4 inhibitors using Structure-Based Drug Design and Quantitative Structure-Activity Relationship techniques. We used bioinformatics tools and biological databases. QSAR study of CDK4 inhibitors has given us an idea of the physicochemical features of studied compounds and their correlation with the IC50 activity. The docking study has helped to highlight the molecule key elements to refine in order to get a more potent compound of CDK4.The Molecule under the code 21366124 which has the low IC50= 3 nmole shows the most binding affinity with a score value of ΔG=-9,8 kcal/mol. As prospects, it would be very interesting to synthesize this drug candidate and to test its inhibitory activity on cell culture of breast cancer.

scholarly journals Anticancer Drug Design: Development of Cyclin-Dependent Kinase Inhibitors Using In Silico Techniques

2020 ◽  
pp. 1-3
Author(s):  
Derouicha Matmour ◽  
◽  
Yassine Mérad ◽  
Nawel Achachi ◽  
Houari Toumi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Design ◽  
Anticancer Drug ◽  
Mammalian Cells ◽  
Drug Candidate ◽  
Biological Databases ◽  
Design Development ◽  
Qsar Study ◽  
Structure Based Drug Design ◽  
Restriction Point

In mammalian cells, proliferation is controlled by the cell cycle, where cyclin-dependent kinases regulate critical checkpoints. CDK4 is considered highly validated anticancer drug target due to its essential role regulating cell cycle progression at the G1 restriction point. Our objective is designing novel CDK4 inhibitors using Structure-Based Drug Design and Quantitative Structure-Activity Relationship techniques. We used bioinformatics tools and biological databases. QSAR study of CDK4 inhibitors has given us an idea on the physicochemical features of studied compounds and their correlation with the IC50 activity. The docking study has helped to highlight the molecule key elements to refine in order to get a more potent compound of CDK4.The Molecule under the code 21366124 which has the low IC50= 3 nmole shows the most binding affinity with score value of ΔG=-9,8 kcal/mol. As prospects, it would be very interesting to synthesize this drug candidate and to test its inhibitory activity on cell culture of breast cancer

scholarly journals Primase p49 mRNA expression is serum stimulated but does not vary with the cell cycle.

1989 ◽  
Vol 9 (5) ◽  
pp. 1940-1945 ◽  
Author(s):  
B Y Tseng ◽  
C E Prussak ◽  
M T Almazan
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Small Subunit ◽  
Mrna Levels ◽  
Proliferating Cells ◽  
Restriction Point ◽  
Serum Stimulation ◽  
G1 Cells

Expression of the small-subunit p49 mRNA of primase, the enzyme that synthesizes oligoribonucleotides for initiation of DNA replication, was examined in mouse cells stimulated to proliferate by serum and in growing cells. The level of p49 mRNA increased approximately 10-fold after serum stimulation and preceded synthesis of DNA and histone H3 mRNA by several hours. Expression of p49 mRNA was not sensitive to inhibition by low concentrations of cycloheximide, which suggested that the increase in mRNA occurred before the restriction point control for cell cycle progression described for mammalian cells and was not under its control. p49 mRNA levels were not coupled to DNA synthesis, as observed for the replication-dependent histone genes, since hydroxyurea or aphidicolin had no effect on p49 mRNA levels when added before or during S phase. These inhibitors did have an effect, however, on the stability of p49 mRNA and increased the half-life from 3.5 h to about 20 h, which suggested an interdependence of p49 mRNA degradation and DNA synthesis. When growing cells were examined after separation by centrifugal elutriation, little difference was detected for p49 mRNA levels in different phases of the cell cycle. This was also observed when elutriated G1 cells were allowed to continue growth and then were blocked in M phase with colcemid. Only a small decrease in p49 mRNA occurred, whereas H3 mRNA rapidly decreased, when cells entered G2/M. These results indicate that the level of primase p49 mRNA is not cell cycle regulated but is present constitutively in proliferating cells.

scholarly journals E2F activity is regulated by cell cycle-dependent changes in subcellular localization.

1997 ◽  
Vol 17 (12) ◽  
pp. 7268-7282 ◽  
Author(s):  
R Verona ◽  
K Moberg ◽  
S Estes ◽  
M Starz ◽  
J P Vernon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Subcellular Localization ◽  
Nuclear Localization ◽  
Mammalian Cells ◽  
Critical Role ◽  
Biological Properties ◽  
Dependent Manner ◽  
Restriction Point ◽  
Cycle Dependent ◽  
Almost All

E2F directs the cell cycle-dependent expression of genes that induce or regulate the cell division process. In mammalian cells, this transcriptional activity arises from the combined properties of multiple E2F-DP heterodimers. In this study, we show that the transcriptional potential of individual E2F species is dependent upon their nuclear localization. This is a constitutive property of E2F-1, -2, and -3, whereas the nuclear localization of E2F-4 is dependent upon its association with other nuclear factors. We previously showed that E2F-4 accounts for the majority of endogenous E2F species. We now show that the subcellular localization of E2F-4 is regulated in a cell cycle-dependent manner that results in the differential compartmentalization of the various E2F complexes. Consequently, in cycling cells, the majority of the p107-E2F, p130-E2F, and free E2F complexes remain in the cytoplasm. In contrast, almost all of the nuclear E2F activity is generated by pRB-E2F. This complex is present at high levels during G1 but disappears once the cells have passed the restriction point. Surprisingly, dissociation of this complex causes little increase in the levels of nuclear free E2F activity. This observation suggests that the repressive properties of the pRB-E2F complex play a critical role in establishing the temporal regulation of E2F-responsive genes. How the differential subcellular localization of pRB, p107, and p130 contributes to their different biological properties is also discussed.

scholarly journals Structure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosis

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Jérémie Piton ◽  
Anthony Vocat ◽  
Andréanne Lupien ◽  
Caroline S. Foo ◽  
Olga Riabova ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Antitubercular Activity ◽  
Cysteine Residue ◽  
Drug Candidate ◽  
Structure Based Drug Design ◽  
Content Type ◽  
Active Site Cysteine ◽  
Covalent Adducts

ABSTRACT Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile, and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ, and covalent adducts with the active-site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group, no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

Thermotolerance of mammalian cells is not induced near the restriction point of the G1 phase of the cell cycle

2006 ◽  
Vol 411 (1) ◽  
pp. 515-516
Author(s):  
A. A. Kudryavtsev ◽  
V. P. Lavrovskaya ◽  
O. A. Pivovarova ◽  
E. I. Lezhnev ◽  
L. M. Chailakhyan
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
G1 Phase ◽  
Restriction Point

scholarly journals Structure-Based Drug Design of an Inhibitor of the SARS-CoV-2 (COVID-19) Main Protease Using Free Software: A Tutorial for Students and Scientists

2020 ◽  
Author(s):  
Sheng Zhang ◽  
Maj Krumberger ◽  
Michael A. Morris ◽  
Chelsea Marie T. Parrocha ◽  
James H. Griffin ◽  
...  
Keyword(s):  
Drug Design ◽  
Cyclic Peptide ◽  
Free Software ◽  
New Drugs ◽  
Peptide Inhibitor ◽  
Drug Candidate ◽  
Crystallographic Structure ◽  
Structure Based Drug Design ◽  
X Ray ◽  
Main Protease

This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (M<sup>pro</sup>) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the M<sup>pro</sup> active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV M<sup>pro</sup> and the highly homologous SARS-CoV-2 M<sup>pro</sup>. The supporting information (supplementary material) provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 M<sup>pro</sup>.

scholarly journals When Yeast Cells Change their Mind: Cell Cycle 'Start' is Reversible under Starvation

2021 ◽  
Author(s):  
Deniz Irvali ◽  
Fabian P. Schlottmann ◽  
Prathibha Muralidhara ◽  
Iliya Nadelson ◽  
N. Ezgi Wood ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Live Cell Imaging ◽  
Feedback Loop ◽  
Cell Imaging ◽  
Yeast Cells ◽  
Nutrient Depletion ◽  
Restriction Point ◽  
Cell Cycle Inhibitor ◽  
Nutrient Signaling

Eukaryotic cells decide in late G1 whether to commit to another round of genome duplication and division. This point of irreversible cell cycle commitment is a molecular switch termed 'Restriction Point' in mammals and 'Start' in budding yeast. At Start, yeast cells integrate multiple signals such as pheromones, osmolarity, and nutrients. If sufficient nutrients are lacking, cells will not pass Start. However, how the cells respond to nutrient depletion after they have made the Start decision, remains poorly understood. Here, we analyze by live cell imaging how post-Start yeast cells respond to nutrient depletion. We monitor fluorescently labelled Whi5, the cell cycle inhibitor whose export from the nucleus determines Start. Surprisingly, we find that cells that have passed Start can re-import Whi5 back into the nucleus. This occurs when cells are faced with starvation up to 20 minutes after Start. In these cells, the positive feedback loop is interrupted, Whi5 re-binds DNA, and CDK activation occurs a second time once nutrients are replenished. Cells which re-import Whi5 also become sensitive to mating pheromone again, and thus behave like pre-Start cells. In summary, we show that upon starvation the commitment decision at Start can be reversed. We therefore propose that in yeast, as has been suggested for mammalian cells, cell cycle commitment is a multi-step process, where irreversibility in face of nutrient signaling is only reached approximately 20 minutes after CDK activation at Start.

Structure Based Drug Design: Development of Potent and Selective Factor IXa (FIXa) Inhibitors

2010 ◽  
Vol 53 (4) ◽  
pp. 1473-1482 ◽  
Author(s):  
Shouming Wang ◽  
Richard Beck ◽  
Andrew Burd ◽  
Toby Blench ◽  
Frederic Marlin ◽  
...  
Keyword(s):  
Drug Design ◽  
Design Development ◽  
Structure Based Drug Design ◽  
Factor Ixa

scholarly journals Cdc48p is required for the cell cycle commitment point at Start via degradation of the G1-CDK inhibitor Far1p

2003 ◽  
Vol 163 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Xinrong Fu ◽  
Christine Ng ◽  
Daorong Feng ◽  
Chun Liang
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Kinase Inhibitor ◽  
Mitotic Cell ◽  
Cyclin Dependent Kinase ◽  
Restriction Point ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cell Cycle Reentry ◽  
Mammalian Homologue ◽  
Cycle Regulation

The budding yeast Cdc48p and its mammalian homologue p97 are involved in many important cellular activities. Because previous cdc48 mutants have exclusive G2/M arrest, Cdc48p was thought to play an essential role only during mitosis. We found that Cdc48p is required for the execution of Start (a yeast cell cycle commitment point equivalent to the restriction point in mammalian cells) in both a normal mitotic cell cycle and cell cycle reentry after mating pheromone withdrawal through degradation of the G1–cyclin-dependent kinase inhibitor Far1p. Our work is the first to uncover novel roles of Cdc48p as a critical cell cycle regulator in G1, and to shed new light on cell cycle regulation of Far1p, which is the first cyclin-dependent kinase inhibitor shown to be a substrate of an essential proteolysis event mediated by Cdc48p.

scholarly journals Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis

2018 ◽  
Author(s):  
Jérémie Piton ◽  
Anthony Vocat ◽  
Andréanne Lupien ◽  
Caroline Foo ◽  
Olga Riabova ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Antitubercular Activity ◽  
Cysteine Residue ◽  
Drug Candidate ◽  
Structure Based Drug Design ◽  
Active Site Cysteine ◽  
Covalent Adducts ◽  
Active Site Cysteine Residue

ABSTRACTMacozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1 thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ back-up program we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulphonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ and covalent adducts with the active site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 as compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

Sign in / Sign up

Export Citation Format

Share Document