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  1. Article ; Online: Forecasting determinants of recurrence in lung cancer patients exploiting various machine learning models.

    Thirunavukkarasu, Muthu Kumar / Karuppasamy, Ramanathan

    Journal of biopharmaceutical statistics

    2022  Volume 33, Issue 3, Page(s) 257–271

    Abstract: Lung cancer recurrence seems to be the most leading cause of death as well as deterioration of lifespan. Proper assessment of the probability of recurrence in early-stage lung cancer is necessary to push up the treatment progress. We therefore employed ... ...

    Abstract Lung cancer recurrence seems to be the most leading cause of death as well as deterioration of lifespan. Proper assessment of the probability of recurrence in early-stage lung cancer is necessary to push up the treatment progress. We therefore employed machine-learning technologies to forecast post-operative recurrence risks using 174 lung cancer patient records. Six classification algorithms logistic regression, SVM, decision tree classification, random forest classification, XGBoost and lightGBM were used to predict the cancer recurrence. The patient samples were divided into training and test group with the split ratio of 3:1 for model generation and the accuracy were validated using k-fold cross-validation method. It is worth noting that the logistic regression model outperformed all the models in both training (Accuracy = 0.82) and test set (Accuracy = 0.79) on k-fold validation. Further, the optimal features (n = 7) identified using the RFE method is certainly helpful to improve the model in a high precision. The imperative risk factors associated with recurrence were identified using three feature selection methods. Importantly, our research showed that age is an important prognostic factor to be considered during the recurrence prediction. Indeed, severe concern on the identified risk factors combined with predictive models assists the physician to reduce the cancer recurrence rate in patients with lung cancer.
    MeSH term(s) Humans ; Neoplasm Recurrence, Local/epidemiology ; Lung Neoplasms/diagnosis ; Lung Neoplasms/epidemiology ; Machine Learning ; Forecasting ; Algorithms
    Language English
    Publishing date 2022-11-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 1131763-2
    ISSN 1520-5711 ; 1054-3406
    ISSN (online) 1520-5711
    ISSN 1054-3406
    DOI 10.1080/10543406.2022.2148162
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Transcriptome profiling and metabolic pathway analysis towards reliable biomarker discovery in early-stage lung cancer.

    Thirunavukkarasu, Muthu Kumar / Ramesh, Priyanka / Karuppasamy, Ramanathan / Veerappapillai, Shanthi

    Journal of applied genetics

    2024  

    Abstract: Earlier diagnosis of lung cancer is crucial for reducing mortality and morbidity in high-risk patients. Liquid biopsy is a critical technique for detecting the cancer earlier and tracking the treatment outcomes. However, noninvasive biomarkers are ... ...

    Abstract Earlier diagnosis of lung cancer is crucial for reducing mortality and morbidity in high-risk patients. Liquid biopsy is a critical technique for detecting the cancer earlier and tracking the treatment outcomes. However, noninvasive biomarkers are desperately needed due to the lack of therapeutic sensitivity and early-stage diagnosis. Therefore, we have utilized transcriptomic profiling of early-stage lung cancer patients to discover promising biomarkers and their associated metabolic functions. Initially, PCA highlights the diversity level of gene expression in three stages of lung cancer samples. We have identified two major clusters consisting of highly variant genes among the three stages. Further, a total of 7742, 6611, and 643 genes were identified as DGE for stages I-III respectively. Topological analysis of the protein-protein interaction network resulted in seven candidate biomarkers such as JUN, LYN, PTK2, UBC, HSP90AA1, TP53, and UBB cumulatively for the three stages of lung cancers. Gene enrichment and KEGG pathway analyses aid in the comprehension of pathway mechanisms and regulation of identified hub genes in lung cancer. Importantly, the medial survival rates up to ~ 70 months were identified for hub genes during the Kaplan-Meier survival analysis. Moreover, the hub genes displayed the significance of risk factors during gene expression analysis using TIMER2.0 analysis. Therefore, we have reason that these biomarkers may serve as a prospective targeting candidate with higher treatment efficacy in early-stage lung cancer patients.
    Language English
    Publishing date 2024-03-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 1235302-4
    ISSN 2190-3883 ; 1234-1983
    ISSN (online) 2190-3883
    ISSN 1234-1983
    DOI 10.1007/s13353-024-00847-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Sequential virtual screening collaborated with machine-learning strategies for the discovery of precise medicine against non-small cell lung cancer.

    Thirunavukkarasu, Muthu Kumar / Veerappapillai, Shanthi / Karuppasamy, Ramanathan

    Journal of biomolecular structure & dynamics

    2023  Volume 42, Issue 2, Page(s) 615–628

    Abstract: Dysregulation of MAPK pathway receptors are crucial in causing uncontrolled cell proliferation in many cancer types including non-small cell lung cancer. Due to the complications in targeting the upstream components, MEK is an appealing target to ... ...

    Abstract Dysregulation of MAPK pathway receptors are crucial in causing uncontrolled cell proliferation in many cancer types including non-small cell lung cancer. Due to the complications in targeting the upstream components, MEK is an appealing target to diminish this pathway activity. Hence, we have aimed to discover potent MEK inhibitors by integrating virtual screening and machine learning-based strategies. Preliminary screening was conducted on 11,808 compounds using the cavity-based pharmacophore model AADDRRR. Further, seven ML models were accessed to predict the MEK active compounds using six molecular representations. The LGB model with morgan2 fingerprints surpasses other models ensuing 0.92 accuracy and 0.83 MCC value versus test set and 0.85 accuracy and 0.70 MCC value with external set. Further, the binding ability of screened hits were examined using glide XP docking and prime-MM/GBSA calculations. Note that we have utilized three ML-based scoring functions to predict the various biological properties of the compounds. The two hit compounds such as DB06920 and DB08010 resulted excellent binding mechanism with acceptable toxicity properties against MEK. Further, 200 ns of MD simulation combined with MM-GBSA/PBSA calculations confirms that DB06920 may have stable binding conformations with MEK thus step forwarded to the experimental studies in the near future.Communicated by Ramaswamy H. Sarma.
    MeSH term(s) Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Molecular Dynamics Simulation ; Protein Binding ; Molecular Docking Simulation ; Early Detection of Cancer ; Lung Neoplasms/drug therapy ; Machine Learning ; Mitogen-Activated Protein Kinase Kinases
    Chemical Substances Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
    Language English
    Publishing date 2023-03-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 49157-3
    ISSN 1538-0254 ; 0739-1102
    ISSN (online) 1538-0254
    ISSN 0739-1102
    DOI 10.1080/07391102.2023.2194994
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Drug repurposing combined with MM/PBSA based validation strategies towards MEK inhibitors screening.

    Thirunavukkarasu, Muthu Kumar / Karuppasamy, Ramanathan

    Journal of biomolecular structure & dynamics

    2021  Volume 40, Issue 22, Page(s) 12392–12403

    Abstract: Emergence of oncogenic mutations in the MAPK pathway gaining more impact in the recent years. Importantly, MEK is a core element of this pathway as it is easy to inhibit and is a gatekeeper of multiple malignancies. Therefore, we ... ...

    Abstract Emergence of oncogenic mutations in the MAPK pathway gaining more impact in the recent years. Importantly, MEK is a core element of this pathway as it is easy to inhibit and is a gatekeeper of multiple malignancies. Therefore, we performed
    MeSH term(s) Humans ; Drug Repositioning ; Nebivolol ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/chemistry ; Mitogen-Activated Protein Kinase Kinases
    Chemical Substances Nebivolol (030Y90569U) ; Protein Kinase Inhibitors ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
    Language English
    Publishing date 2021-08-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 49157-3
    ISSN 1538-0254 ; 0739-1102
    ISSN (online) 1538-0254
    ISSN 0739-1102
    DOI 10.1080/07391102.2021.1970629
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Computational biophysics approach towards the discovery of multi-kinase blockers for the management of MAPK pathway dysregulation.

    Thirunavukkarasu, Muthu Kumar / Veerappapillai, Shanthi / Karuppasamy, Ramanathan

    Molecular diversity

    2022  Volume 27, Issue 5, Page(s) 2093–2110

    Abstract: The MAPK pathway is important in human lung cancer and is improperly activated in a substantial proportion through number of ways. Strategies on dual-targeting RAF and MEK are an alternative option to diminish the limitations in this pathway inhibition. ... ...

    Abstract The MAPK pathway is important in human lung cancer and is improperly activated in a substantial proportion through number of ways. Strategies on dual-targeting RAF and MEK are an alternative option to diminish the limitations in this pathway inhibition. Hence, we implemented parallel pharmacophore screening of 11,808 DrugBank compounds against RAF and MEK. ADHRR and DHHRR were modeled as a pharmacophore hypothesis for RAF and MEK respectively. Importantly, these hypotheses resulted an AUC value of > 0.90 with the external data set. As a result of phase screening, glide docking, and prime-MM/GBSA scoring, it is determined that DB08424 and DB08907 have the best chances of acting as multi-kinase inhibitors. The pi-cation interaction with key amino acid residues of both target receptors may responsible for the stronger binding with these kinases. Cumulative 600 ns MD simulation studies validate the binding ability of these compounds. Significantly, the hit compounds resulted higher number of stable conformational state with less atomic movements than the reference compound against both targets. The anti-cancer efficacy of the lead compounds was validated through machine learning-based approaches. These findings suggest that DB08424 and DB08907 might be novel molecules to be explored further experimentally to block the MAPK signaling in lung cancer patients.
    MeSH term(s) Humans ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Protein Binding ; Lung Neoplasms ; Mitogen-Activated Protein Kinase Kinases
    Chemical Substances Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
    Language English
    Publishing date 2022-10-19
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1376507-3
    ISSN 1573-501X ; 1381-1991
    ISSN (online) 1573-501X
    ISSN 1381-1991
    DOI 10.1007/s11030-022-10545-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Exploring safe and potent bioactives for the treatment of non-small cell lung cancer.

    Thirunavukkarasu, Muthu Kumar / Shin, Woong-Hee / Karuppasamy, Ramanathan

    3 Biotech

    2021  Volume 11, Issue 5, Page(s) 241

    Abstract: Activating and suppressing mutations in the MAPK pathway receptors are the primary causes of NSCLC. Of note, MEK inhibition is considered a promising strategy because of the diverse structures and harmful effects of upstream receptors in MAPK pathway. ... ...

    Abstract Activating and suppressing mutations in the MAPK pathway receptors are the primary causes of NSCLC. Of note, MEK inhibition is considered a promising strategy because of the diverse structures and harmful effects of upstream receptors in MAPK pathway. Thus, we explore a total of 1574 plant-based bioactive compounds activity against MEK using an energy-based virtual screening strategy. Molecular docking, binding free energy, and drug-likeness analysis were performed through GLIDE, Prime MM-GBSA, and QikProp module, respectively. The findings indicate that 5-O-caffeoylshikimic acid has an increased binding affinity to MEK protein. Further, molecular dynamic simulations and MM-PBSA analysis were performed to explore the ligand activity in real-life situations. In essence, compounds inhibitory activity was validated across 77 lung cancer cell lines using multimodal attention-based neural network algorithm. Eventually, our analysis highlight that 5-O-caffeoylshikimic acid obtained from the bark of
    Language English
    Publishing date 2021-04-26
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2600522-0
    ISSN 2190-5738 ; 2190-572X
    ISSN (online) 2190-5738
    ISSN 2190-572X
    DOI 10.1007/s13205-021-02797-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Exploring safe and potent bioactives for the treatment of non-small cell lung cancer

    Thirunavukkarasu, Muthu Kumar / Shin, Woong-Hee / Karuppasamy, Ramanathan

    3 Biotech. 2021 May, v. 11, no. 5

    2021  

    Abstract: Activating and suppressing mutations in the MAPK pathway receptors are the primary causes of NSCLC. Of note, MEK inhibition is considered a promising strategy because of the diverse structures and harmful effects of upstream receptors in MAPK pathway. ... ...

    Abstract Activating and suppressing mutations in the MAPK pathway receptors are the primary causes of NSCLC. Of note, MEK inhibition is considered a promising strategy because of the diverse structures and harmful effects of upstream receptors in MAPK pathway. Thus, we explore a total of 1574 plant-based bioactive compounds activity against MEK using an energy-based virtual screening strategy. Molecular docking, binding free energy, and drug-likeness analysis were performed through GLIDE, Prime MM-GBSA, and QikProp module, respectively. The findings indicate that 5-O-caffeoylshikimic acid has an increased binding affinity to MEK protein. Further, molecular dynamic simulations and MM-PBSA analysis were performed to explore the ligand activity in real-life situations. In essence, compounds inhibitory activity was validated across 77 lung cancer cell lines using multimodal attention-based neural network algorithm. Eventually, our analysis highlight that 5-O-caffeoylshikimic acid obtained from the bark of Rhizoma smilacis glabrae would be developed as a potential compound for treating NSCLC.
    Keywords Gibbs free energy ; algorithms ; bark ; bioactive compounds ; ligands ; lung neoplasms ; neoplasm cells ; rhizomes
    Language English
    Dates of publication 2021-05
    Size p. 241.
    Publishing place Springer International Publishing
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 2600522-0
    ISSN 2190-5738 ; 2190-572X
    ISSN (online) 2190-5738
    ISSN 2190-572X
    DOI 10.1007/s13205-021-02797-6
    Database NAL-Catalogue (AGRICOLA)

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  8. Article: In Silico Screening of Available Drugs Targeting Non-Small Cell Lung Cancer Targets: A Drug Repurposing Approach.

    Thirunavukkarasu, Muthu Kumar / Suriya, Utid / Rungrotmongkol, Thanyada / Karuppasamy, Ramanathan

    Pharmaceutics

    2021  Volume 14, Issue 1

    Abstract: The RAS-RAF-MEK-ERK pathway plays a key role in malevolent cell progression in many tumors. The high structural complexity in the upstream kinases limits the treatment progress. Thus, MEK inhibition is a promising strategy since it is easy to inhibit and ...

    Abstract The RAS-RAF-MEK-ERK pathway plays a key role in malevolent cell progression in many tumors. The high structural complexity in the upstream kinases limits the treatment progress. Thus, MEK inhibition is a promising strategy since it is easy to inhibit and is a gatekeeper for the many malignant effects of its downstream effector. Even though MEK inhibitors are under investigation in many cancers, drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. Hence, we accomplished a high-throughput virtual screening to overcome this bottleneck by the discovery of dual-targeting therapy in cancer treatment. Here, a total of 11,808 DrugBank molecules were assessed through high-throughput virtual screening for their activity against MEK. Further, the Glide docking, MLSF and prime-MM/GBSA methods were implemented to extract the potential lead compounds from the database. Two compounds, DB012661 and DB07642, were outperformed in all the screening analyses. Further, the study results reveal that the lead compounds also have a significant binding capability with the co-target PIM1. Finally, the SIE-based free energy calculation reveals that the binding of compounds was majorly affected by the van der Waals interactions with MEK receptor. Overall, the in silico binding efficacy of these lead compounds against both MEK and PIM1 could be of significant therapeutic interest to overcome drug resistance in the near future.
    Language English
    Publishing date 2021-12-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics14010059
    Database MEDical Literature Analysis and Retrieval System OnLINE

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