scholarly journals Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Md Shahinozzaman ◽  
Sinthyia Ahmed ◽  
Rashiduzzaman Emran ◽  
Shinkichi Tawata
Keyword(s):  
Density Functional ◽  
Dynamics Simulation ◽  
Allosteric Site ◽  
Allosteric Interactions ◽  
Anticancer Effects ◽  
Toxic Drug ◽  
Crystal Density ◽  
Anti Cancer

AbstractP21-activated kinases (PAKs) are serine/threonine protein kinase which have six different isoforms (PAK1–6). Of those, PAK1 is overexpressed in many cancers and considered to be a major chemotherapeutic target. Most of the developed PAK1 inhibitor drugs work as pan-PAK inhibitors and show undesirable toxicity due to having untargeted kinase inhibition activities. Selective PAK1 inhibitors are therefore highly desired and oncogenic drug hunters are trying to develop allosteric PAK1 inhibitors. We previously synthesized 1,2,3-triazolyl ester of ketorolac (15K) through click chemistry technique, which exhibits significant anti-cancer effects via inhibiting PAK1. Based on the selective anticancer effects of 15K against PAK1-dependent cancer cells, we hypothesize that it may act as an allosteric PAK1 inhibitor. In this study, computational analysis was done with 15K to explore its quantum chemical and thermodynamic properties, molecular interactions and binding stability with PAK1, physicochemical properties, ADMET, bioactivities, and druglikeness features. Molecular docking analysis demonstrates 15K as a potent allosteric ligand that strongly binds to a novel allosteric site of PAK1 (binding energy ranges – 8.6 to – 9.2 kcal/mol) and does not target other PAK isoforms; even 15K shows better interactions than another synthesized PAK1 inhibitor. Molecular dynamics simulation clearly supports the stable binding properties of 15K with PAK1 crystal. Density functional theory-based calculations reveal that it can be an active drug with high softness and moderate polarity, and ADMET predictions categorize it as a non-toxic drug as evidenced by in vitro studies with brine shrimp and fibroblast cells. Structure–activity relationship clarifies the role of ester bond and triazol moiety of 15K in establishing novel allosteric interactions. Our results summarize that 15K selectively inhibits PAK1 as an allosteric inhibitor and in turn shows anticancer effects without toxicity.

Computational prediction of small molecules with predicted binding to FGFR3 and testing biological effects in bone cells

2021 ◽  
pp. 153537022110021
Author(s):  
Subburaman Mohan ◽  
Karthikeyan Muthusamy ◽  
Selvaraman Nagamani ◽  
Chandrasekhar Kesavan
Keyword(s):  
Bone Formation ◽  
Small Molecules ◽  
Density Functional ◽  
Absorption Rate ◽  
Oral Absorption ◽  
Bone Cells ◽  
Biological Effects ◽  
Dynamics Simulation ◽  
Molecular Stability

Activating anabolic receptor-mediated signaling is essential for stimulating new bone formation and for promoting bone healing in humans. Fibroblast growth factor receptor (FGFR) 3 is reported to be an important positive regulator of osteogenesis. Presently, recombinant proteins are used to stimulate FGFR3 function but have limitations for therapy due to expense and stability. Therefore, there is a need for identification of novel small molecules binding to FGFR3 that promote biological function. In silico molecular docking and high-throughput virtual screening on zinc database identified seven compounds predicted to bind to an active site within the βCʹ-βE loop, specific to FGFR3. All seven compounds fall within an acceptable range of ADME/T properties. Four compounds showed a 30–65% oral absorption rate. Density functional theory analysis revealed a high HOMO-LUMO gap, reflecting high molecular stability for compounds 14977614 and 13509082. Five compounds exhibited mutagenicity, while the other three compounds presented irritability. Computational mutagenesis predicted that mutating G322 affected compound binding to FGFR3. Molecular dynamics simulation revealed compound 14977614 is stable in binding to FGFR3. Furthermore, compound 14977614, with an oral absorption rate of 60% and high molecular stability, produced significant increases in both proliferation and differentiation of bone marrow stromal cells in vitro. Anti-FGFR3 treatment completely blocked the stimulatory effect of 14977614 on BMSC proliferation. Ex vivo treatment of mouse calvaria in organ culture for seven days with 14977614 increased mineralization and expression levels of bone formation markers. In conclusion, computational analyses identified seven compounds that bind to the FGFR3, and in vitro studies showed that compound 14977614 exerts significant biological effects on osteogenic cells.

scholarly journals Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro

Blood ◽  
1983 ◽  
Vol 61 (5) ◽  
pp. 889-893 ◽  
Author(s):  
WT Gerson ◽  
DG Fine ◽  
SP Spielberg ◽  
LL Sensenbrenner
Keyword(s):  
Cell Viability ◽  
Aplastic Anemia ◽  
Adverse Reactions ◽  
Drug Metabolites ◽  
Peripheral Lymphocytes ◽  
Toxic Drug ◽  
Arene Oxide ◽  
Increased Susceptibility

A 53-yr-old man sequentially developed aplastic anemia from phenytoin and carbamazepine. Both compounds undergo metabolism to potentially toxic arene oxide intermediates. We tested the hypothesis that the patient's adverse reactions were due to a defect in detoxification of such metabolites by challenging his peripheral lymphocytes with drug metabolites generated by a murine hepatic microsomal system in vitro. The patient's cell viability was normal in the absence of drugs. However, his cells showed greater toxicity from both phenytoin and carbamazepine metabolites than did controls. Toxicity was dependent on microsomes and NADPH. Intermediate toxicity was noted in cells from the patient's mother. The results provide the first evidence for a role of arene oxide drug metabolites in aplastic anemia in humans and suggest that enhanced susceptibility to toxicity may be based on an inherited abnormality in metabolite detoxification.

In vitro evaluation and molecular dynamics, DFT guided investigation of antimalarial activity of ethnomedicinally used Coptis teeta Wall

2021 ◽  
Vol 24 ◽  
Author(s):  
Ashis Kumar Goswami ◽  
Hemanta Kumar Sharma ◽  
Neelutpal Gogoi ◽  
Ankita Kashyap ◽  
Bhaskar Jyoti Gogoi
Keyword(s):  
Molecular Dynamics ◽  
In Silico ◽  
Density Functional ◽  
Antimalarial Activity ◽  
In Silico Analysis ◽  
Dynamics Simulation ◽  
Discovery Studio ◽  
North East ◽  
Silico Analysis

Background: Malaria is caused by different species of Plasmodium; among which P. falciparum is the most severe. Coptis teeta is an ethnomedicinal plant of enormous importance for tribes of north east India. Objective: In this study, the anti malarial activity of the methanol extracts of Coptis teeta was evaluated in vitro and lead identification via in silico study. Method: On the basis of the in vitro results, in silico analysis by application of different modules of Discovery Studio 2018 was performed on multiple targets of P. falciparum taking into consideration some of the compounds reported from C. teeta. Results: The IC50 of the methanol extract of Coptis teeta 0.08 µg/ml in 3D7 strain and 0.7 µg/ml in Dd2 strain of P. falciparum. From the docking study, noroxyhydrastatine was observed to have better binding affinity in comparison to chloroquine. The binding of noroxyhydrastinine with dihydroorotate dehydrogenase was further validated by molecular dynamics simulation and was observed to be significantly stable in comparison to the co-crystal inhibitor. During simulations it was observed that noroxyhydrastinine retained the interactions, giving strong indications of its effectiveness against the P. falciparum proteins and stability in the binding pocket. From the Density-functional theory analysis, the band gap energy of noroxyhydrastinine was found to be 0.186 Ha indicating a favourable interaction. Conclusion: The in silico analysis as an addition to the in vitro results provide strong evidence of noroxyhydrastinine as an anti malarial agent.

Role of Pentacyclic Triterpenoid Acids in the Treatment of Bladder Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Anindita Ghosh ◽  
Chinmay Kumar Panda
Keyword(s):  
Bladder Cancer ◽  
In Vivo Studies ◽  
Pentacyclic Triterpenoids ◽  
Pentacyclic Triterpenoid ◽  
Anticancer Effects ◽  
Antitumor Compounds ◽  
Resistance To Chemotherapy

: Bladder cancer carries a poor prognosis and has proven resistance to chemotherapy. Pentacyclic Triterpenoid Acids (PTAs) are natural bioactive compounds that have a well-known impact on cancer research because of their cytotoxic and chemopreventive activities. This review focuses on bladder cancer which can no longer be successfully treated by DNA damaging drugs. Unlike most of the existing drugs against bladder cancer, PTAs are non-toxic to normal cells. Collecting findings from both in vitro and in vivo studies, it has been concluded that PTAs may serve as promising agents in future bladder cancer therapy. In this review, the roles of various PTAs in bladder cancer have been explored, and their mechanisms of action in the treatment of bladder cancer have been described. Specific PTAs have been shortlisted from each of the chief skeletons of pentacyclic triterpenoids, which could be effective against bladder cancer because of their mode of action. This review thereby throws light on the multi targets and mechanisms of PTAs, which are responsible for their selective anticancer effects and provides guidelines for further research and development of new natural antitumor compounds.

scholarly journals The chaperone Hsp70 is a BH3 receptor activated by the pro-apoptotic Bim to stabilize anti-apoptotic clients

2020 ◽  
Vol 295 (37) ◽  
pp. 12900-12909
Author(s):  
Zongwei Guo ◽  
Ting Song ◽  
Ziqian Wang ◽  
Donghai Lin ◽  
Keke Cao ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Cell Fate ◽  
Protein Misfolding ◽  
Structural Basis ◽  
Titration Calorimetry ◽  
Allosteric Site ◽  
Transverse Relaxation ◽  
Bh3 Domain

The chaperone heat shock protein 70 (Hsp70) is crucial for avoiding protein misfolding under stress, but is also up-regulated in many kinds of cancers, where its ability to buffer cellular stress prevents apoptosis. Previous research has suggested Hsp70 interacts with pro-apoptotic Bcl-2 family proteins, including Bim and Bax. However, a definitive demonstration of this interaction awaits, and insights into the structural basis and molecular mechanism remain unclear. Earlier studies have identified a Bcl-2 homology 3 (BH3) domain present in Bcl-2 family members that engages receptors to stimulate apoptosis. We now show that Hsp70 physically interacts with pro-apoptotic multidomain and BH3-only proteins via a BH3 domain, thereby serving as a novel BH3 receptor, using in vitro fluorescent polarization (FP), isothermal titration calorimetry (ITC), and cell-based co-immunoprecipitation (co-IP) experiments, 1H-15N-transverse relaxation optimized spectroscopy (TROSY-HSQC), trypsin proteolysis, ATPase activity, and denatured rhodanese aggregation measurements further demonstrated that BimBH3 binds to a novel allosteric site in the nucleotide-binding domain (NBD) of Hsp70, by which Bim acts as a positive co-chaperone to promote the ATPase activity and chaperone functions. A dual role of Hsp70's anti-apoptotic function was revealed that when it keeps Bim in check to inhibit apoptosis, it simultaneously stabilizes oncogenic clients including AKT and Raf-1 with the aid of Bim. Two faces of Bim in cell fate regulation were revealed that in opposite to its well-established pro-apoptotic activator role, Bim could help the folding of oncogenic proteins.

Thymoquinone and its nanoformulation attenuate colorectal and breast cancers and alleviate doxorubicin-induced cardiotoxicity

Nanomedicine ◽  
2021 ◽  
Author(s):  
Ali H El-Far ◽  
Taher A Salaheldin ◽  
Kavitha Godugu ◽  
Noureldien HE Darwish ◽  
Shaker A Mousa
Keyword(s):  
Xenograft Model ◽  
Double Emulsion ◽  
Tumor Model ◽  
Breast Cancers ◽  
Anti Cancer ◽  
Xenograft Tumor Model ◽  
Average Size ◽  
Hct116 Cells

Aim: To investigate the anti-cancer potential of thymoquinone (TQ) and TQ nanoparticles (TQ-NPs) and their protection against doxorubicin (DOX)-induced cardiotoxicity. Methods: TQ-NPs were prepared by double emulsion method and characterized. The efficacy of TQ and TQ-DOX was studied against HCT116 and MDA-MB-231-Luc cancer cell lines in vitro and in a xenograft tumor model. Results: TQ and TQ + DOX increased Bax levels in HCT116 cells and decreased Bcl2 levels in MDA-MB-231-Luc cells. In the xenograft model, the TQ-NPs, with an average size of 218 nm, in combination with DOX, significantly reduced tumor size. The combination of TQ or TQ-NPs with DOX significantly reduced DOX-induced cardiotoxicity. Conclusion: Data suggest the promising role of TQ and TQ-NPs alone and with DOX for anti-cancer and cardiac protection benefits.

The Role of PI3K and Wntsignaling Pathways and CSC Markers in Melanoma (B16F10) Therapy

2021 ◽  
Author(s):  
marjan hajimoradi javarsiani ◽  
javad sajedianfard ◽  
Shagayegh Haghjooy Javanmard ◽  
Micol Eleonora Fiori
Keyword(s):  
Cancer Progression ◽  
Therapeutic Agent ◽  
B16f10 Melanoma ◽  
Melanoma Cancer ◽  
Anti Cancer ◽  
Melanoma B16f10 ◽  
The Subject ◽  
Cell Growth And Proliferation

Abstract Background Metformin has been the subject of recent studies aimed at the treatment of melanoma cancer. In this study, the anti-cancer effects of metformin, an antidiabetic drug, was investigated in-vitrousing the B16F10 melanoma cell line. Methods Melanoma cells were treated for 24 h with various concentrations of metformin, alone or incombination withdacarbazine. The effects of these two treatment agents on cell viability were evaluated by MTT assay. In addition, stemness and the activation of specific signaling pathways were evaluated by FACS and immunoblotting. Results Metformin induced β-catenin phosphorylation and decreasedmTOR and PARP expressions. Also, a normal dose of metformin was found toreducethe phosphorylation levels of4E-BP1, AKT, and S6rp.In this study, we evaluated the potential of metformin as a therapeutic agent against CSCs in the adjuvant setting. Conclusion Our data indicate that some transcriptional regulators and proteins in the above-mentioned pathwayswere associated with cancer progression and inhibited by adjuvant chemotherapy with metformin.Metformin significantly inhibited cell growth and proliferation pathways, including Wnt and PI3K/AKT/mTOR. These findings show the potential of metformin in cancer treatment.

Distinct functional roles of the two terminal halves of eukaryotic phosphofructokinase

2012 ◽  
Vol 445 (2) ◽  
pp. 213-218 ◽  
Author(s):  
Oscar H. Martínez-Costa ◽  
Valentina Sánchez ◽  
Antonio Lázaro ◽  
Eloy D. Hernández ◽  
Keith Tornheim ◽  
...  
Keyword(s):  
Active Site ◽  
Kinetic Properties ◽  
Wild Type ◽  
Allosteric Site ◽  
Functional Roles ◽  
Allosteric Interactions ◽  
C Terminus ◽  
N Terminus ◽  
Metabolite Binding

Eukaryotic PFK (phosphofructokinase), a key regulatory enzyme in glycolysis, has homologous N- and C-terminal domains thought to result from duplication, fusion and divergence of an ancestral prokaryotic gene. It has been suggested that both the active site and the Fru-2,6-P2 (fructose 2,6-bisphosphate) allosteric site are formed by opposing N- and C-termini of subunits orientated antiparallel in a dimer. In contrast, we show in the present study that in fact the N-terminal halves form the active site, since expression of the N-terminal half of the enzymes from Dictyostelium discoideum and human muscle in PFK-deficient yeast restored growth on glucose. However, the N-terminus alone was not stable in vitro. The C-terminus is not catalytic, but is needed for stability of the enzyme, as is the connecting peptide that normally joins the two domains (here included in the N-terminus). Co-expression of homologous, but not heterologous, N- and C-termini yielded stable fully active enzymes in vitro with sizes and kinetic properties similar to those of the wild-type tetrameric enzymes. This indicates that the separately translated domains can fold sufficiently well to bind to each other, that such binding of complementary domains is stable and that the alignment is sufficiently accurate and tight as to preserve metabolite binding sites and allosteric interactions.

scholarly journals Oxymatrine Attenuates Tumor Growth and Deactivates STAT5 Signaling in a Lung Cancer Xenograft Model

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 49 ◽  
Author(s):  
Young Yun Jung ◽  
Muthu K. Shanmugam ◽  
Acharan S. Narula ◽  
Chulwon Kim ◽  
Jong Hyun Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Mouse Model ◽  
A549 Cells ◽  
Xenograft Model ◽  
Signaling Cascade ◽  
Anticancer Effects ◽  
Anti Cancer

Oxymatrine (OMT) is a major alkaloid found in radix Sophorae flavescentis extract and has been reported to exhibit various pharmacological activities. We elucidated the detailed molecular mechanism(s) underlying the therapeutic actions of OMT in non-small cell lung cancer (NSCLC) cells and a xenograft mouse model. Because the STAT5 signaling cascade has a significant role in regulating cell proliferation and survival in tumor cells, we hypothesized that OMT may disrupt this signaling cascade to exert its anticancer effects. We found that OMT can inhibit the constitutive activation of STAT5 by suppressing the activation of JAK1/2 and c-Src, nuclear localization, as well as STAT5 binding to DNA in A549 cells and abrogated IL-6-induced STAT5 phosphorylation in H1299 cells. We also report that a sub-optimal concentration of OMT when used in combination with a low dose of paclitaxel produced significant anti-cancer effects by inhibiting cell proliferation and causing substantial apoptosis. In a preclinical lung cancer mouse model, OMT when used in combination with paclitaxel produced a significant reduction in tumor volume. These results suggest that OMT in combination with paclitaxel can cause an attenuation of lung cancer growth both in vitro and in vivo.

scholarly journals Rheumatoid Factor: A Novel Determiner in Cancer History

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 591
Author(s):  
Alessio Ugolini ◽  
Marianna Nuti
Keyword(s):  
Rheumatoid Factors ◽  
Chronic Infections ◽  
Cancer History ◽  
Transient Event ◽  
Effector Functions ◽  
Physiological Conditions ◽  
Diagnosis And Prognosis ◽  
Anti Cancer

The possible interplay between autoimmunity and cancer is a topic that still needs to be deeply explored. Rheumatoid factors are autoantibodies that are able to bind the constant regions (Fc) of immunoglobulins class G (IgGs). In physiological conditions, their production is a transient event aimed at contributing to the elimination of pathogens as well as limiting a redundant immune response by facilitating the clearance of antibodies and immune complexes. Their production can become persistent in case of different chronic infections or diseases, being for instance a fundamental marker for the diagnosis and prognosis of rheumatoid arthritis. Their presence is also associated with aging. Some studies highlighted how elevated levels of rheumatoid factors (RFs) in the blood of patients are correlated with an increased cancer risk, tumor recurrence, and load and with a reduced response to anti-tumor immunotherapies. In line with their physiological roles, RFs showed in different works the ability to impair in vitro anti-cancer immune responses and effector functions, suggesting their potential immunosuppressive activity in the context of tumor immunity. Thus, the aim of this review is to investigate the emerging role of RFs as determiners of cancer faith.

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