Udhaya Kumar
@bcm.edu
Post Doctoral Research Scientist
Baylor College of Medicine
RESEARCH, TEACHING, or OTHER INTERESTS
Cancer Research, Endocrinology, General Biochemistry, Genetics and Molecular Biology, Structural Biology
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Zainularifeen Abduljaleel, Sami Melebari, Mohammad Athar, Saied Dehlawi, S. Udhaya Kumar, Syed A. Aziz, Anas Ibrahim Dannoun, Shaheer M. Malik, Jasheela Thasleem, and C. George Priya Doss
Elsevier BV
Sudharsana Sundarrajan, Arthi Venkatesan, Udhaya Kumar S, Mohanraj Gopikrishnan, Iftikhar Aslam Tayubi, M Aditya, Gowrishankar Bychapur Siddaiah, C. George Priya Doss, and Hatem Zayed
Springer Science and Business Media LLC
AbstractAlzheimer disease (AD) is a leading cause of dementia in elderly patients who continue to live between 3 and 11 years of diagnosis. A steep rise in AD incidents is observed in the elderly population in East-Asian countries. The disease progresses through several changes, including memory loss, behavioural issues, and cognitive impairment. The etiology of AD is hard to determine because of its complex nature. The whole exome sequences of late-onset AD (LOAD) patients of Korean origin are investigated to identify rare genetic variants that may influence the complex disorder. Computational annotation was performed to assess the function of candidate variants in LOAD. The in silico pathogenicity prediction tools such as SIFT, Polyphen-2, Mutation Taster, CADD, LRT, PROVEAN, DANN, VEST3, fathmm-MKL, GERP + + , SiPhy, phastCons, and phyloP identified around 17 genes harbouring deleterious variants. The variants in the ALDH3A2 and RAD54B genes were pathogenic, while in 15 other genes were predicted to be variants of unknown significance. These variants can be potential risk candidates contributing to AD. In silico computational techniques such as molecular docking, molecular dynamic simulation and steered molecular dynamics were carried out to understand the structural insights of RAD54B with ATP. The simulation of mutant (T459N) RAD54B with ATP revealed reduced binding strength of ATP at its binding site. In addition, lower binding free energy was observed when compared to the wild-type RAD54B. Our study shows that the identified uncommon variants are linked to AD and could be probable predisposing genetic factors of LOAD.
Finola Priyadharshini Chandrasekaran, Adarsh Vishal, Udita Arora, Udhaya Kumar S., Priya Doss George C., and Everette Jacob Remington Nelson
Wiley
AbstractMutations in the αIIb β‐propeller domain have long been known to disrupt heterodimerization and intracellular trafficking of αIIbβ3 complexes leading to diminished surface expression and/or function, resulting in Glanzmann thrombasthenia. Our previous study on three β‐propeller mutations, namely G128S, S287L, and G357S, showed variable defects in protein transport correlated with the patient's clinical phenotypes. Pulse‐chase experiments revealed differences in αIIbβ3 complex maturation among the three mutations. Hence, the current study aims to correlate conformational changes caused by each one of them. Evolutionary conservation analysis, stability analysis, and molecular dynamics simulations of the three mutant structures were carried out. Stability analysis revealed that, while G128S and G357S mutations destabilized the β‐propeller structure, S287L retained the stability. Wild‐type and mutant β‐propeller structures, when subjected to molecular dynamics simulations, confirmed that G128S and G357S were both destabilizing in nature when compared with the wild‐type and S287L based on several parameters studied, like RMSD, RMSF, Rg, FEL, PCA, secondary structure, and hydrogen bonds. In our previous study, we demonstrated that mutant S287L αIIbβ3 complexes were more stable than the wild‐type αIIbβ3 complexes, as evidenced in pulse‐chase experiments. These findings corroborate variable intracellular fates of mutant αIIbβ3 complexes as a result of these β‐propeller mutations.
M. Anusha, V. Tejaswini, S. Udhaya Kumar, C.N. Prashantha, Karthick Vasudevan, and C. George Priya Doss
Elsevier BV
Hephzibah Cathryn R., Udhaya Kumar S., Gnanasambandan R., P. Jeyaprakash Naayanan, P. Sathiyarajeswaren, M. S. Shree Devi, Satish Srinivas K., and George Priya Doss C.
Wiley
AbstractIn peripheral blood, cell‐free DNA (cfDNA) contains circulating tumor DNA (ctDNA), which indicates molecular abnormalities in metastatic breast tumor tissue. The sequencing of cfDNA of Metastatic Breast Cancer (MBC) patients allows assessment of therapy response and noninvasive treatment. In the proposed study, clinically significant alterations in PIK3CA and TP53 genes associated with MBC resulting in a missense substitution of His1047Arg and Arg282Trp from an next‐generation sequencing‐based multi‐gene panel were reported in a cfDNA of a patient with MBC. To investigate the impact of the reported mutation, we used molecular docking, molecular dynamics simulation, network analysis, and pathway analysis. Molecular Docking analysis determined the distinct binding pattern revealing H1047R‐ATP complex has a higher number of Hydrogen bonds (H‐bonds) and binding affinity with a slight difference compared to the PIK3CA‐ATP complex. Following, molecular dynamics simulation for 200 ns, of which H1047R‐ATP complex resulted in the instability of PIK3CA. Similarly, for TP53 mutant R282W, the zinc‐free state (apo) and zinc‐bounded (holo) complexes were investigated for conformational change between apo and holo complexes, of which the holo complex mutant R282W was unstable. To validate the conformational change of PIK3CA and TP53, 80% mutation of H1047R in the kinase domain of p110α expressed ubiquitously in PIK3CA protein that alters PI3K pathway, while R282W mutation in DNA binding helix (H2) region of P53 protein inhibits the transcription factor in P53 pathway causing MBC. According to our findings, the extrinsic (hypoxia, oxidative stress, and acidosis); intrinsic factors (MYC amplification) in PIK3CA and TP53 mutations will provide potential insights for developing novel therapeutic methods for MBC therapy.
Fatemeh Rahimi Gharemirshamloo, Ranabir Majumder, Udhaya Kumar S., George Priya Doss C., Kourosh Bamdad, Fateme Frootan, and Cemal Un
Wiley
AbstractThe human prion protein gene (PRNP) is mapped to the short arm of chromosome 20 (20pter‐12). Prion disease is associated with mutations in the prion protein‐encoding gene sequence. Earlier studies found that the mutation G127V in the PRNP increases protein stability. In contrast, the mutation E200K, which has the highest mutation rate in the prion protein, causes Creutzfeldt–Jakob disease (CJD) in humans and induces protein aggregation. We aimed to identify the structural mechanisms of E200k and G127V mutations causing CJD. We used a variety of bioinformatic algorithms, including SIFT, PolyPhen, I‐Mutant, PhD‐SNP, and SNP& GO, to predict the association of the E200K mutation with prion disease. MD simulation is performed, and graphs for root mean square deviation, root mean square fluctuation, radius of gyration, DSSP, principal component analysis, porcupine, and free energy landscape are generated to confirm and prove the stability of the wild‐type and mutant protein structures. The protein is analyzed for aggregation, and the results indicate more fluctuations in the protein structure during the simulation owing to the E200K mutation; however, the G127V mutation makes the protein structure stable against aggregation during the simulation.
Udhaya Kumar. S, Rinku Polachirakkal Varghese, V. Anu Preethi, C. George Priya Doss, and Hatem Zayed
IMR Press
BACKGROUND
Mutations in the K-Ras gene are among the most frequent genetic alterations in various cancers, and inhibiting RAS signaling has shown promising results in treating solid tumors. However, finding effective drugs that can bind to the RAS protein remains challenging. This drove us to explore new compounds that could inhibit tumor growth, particularly in cancers that harbor K-Ras mutations.
METHODS
Our study used bioinformatic techniques such as E-pharmacophore virtual screening, molecular simulation, principal component analysis (PCA), extra precision (XP) docking, and ADMET analyses to identify potential inhibitors for K-Ras mutants G12C and G12D.
RESULTS
In our study, we discovered that inhibitors such as afatinib, osimertinib, and hydroxychloroquine strongly inhibit the G12C mutant. Similarly, hydroxyzine, zuclopenthixol, fluphenazine, and doxapram were potent inhibitors for the G12D mutant. Notably, all six of these molecules exhibit a high binding affinity for the H95 cryptic groove present in the mutant structure. These molecules exhibited a unique affinity mechanism at the molecular level, which was further enhanced by hydrophobic interactions. Molecular simulations and PCA revealed the formation of stable complexes within switch regions I and II. This was particularly evident in three complexes: G12C-osimertinib, G12D-fluphenazine, and G12D-zuclopenthixol. Despite the dynamic nature of switches I and II in K-Ras, the interaction of inhibitors remained stable. According to QikProp results, the properties and descriptors of the selected molecules fell within an acceptable range compared to sotorasib.
CONCLUSIONS
We have successfully identified potential inhibitors of the K-Ras protein, laying the groundwork for the development of targeted therapies for cancers driven by K-Ras mutations.
P.A. Trisha Mary, K. Veena Gayathri, P. Senthil Kumar, Revathy Rajagopal, R. Kavitha, Udhaya Kumar. S, C. George Priya Doss, and Gayathri Rangasamy
Springer Science and Business Media LLC
J. Mary Isabella Sonali, K. Veena Gayathri, P. Senthil Kumar, Gayathri Rangasamy, C. S. Poorva, S. Udhaya Kumar, C. George Priya Doss, and R. Gnanasambandan
Springer Science and Business Media LLC
Ambritha Balasundaram, Sriroopreddy Ramireddy, Udhaya Kumar S., Thirumal Kumar D., Iftikhar Aslam Tayubi, Hatem Zayed, and George Priya Doss C.
Informa UK Limited
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by insufficient aspartylglucosaminidase (AGA) activity leading to chronic neurodegeneration. We utilized the PhosphoSitePlus tool to identify the AGA protein's phosphorylation sites. The phosphorylation was induced on the specific residue of the three-dimensional AGA protein, and the structural changes upon phosphorylation were studied via molecular dynamics simulation. Furthermore, the structural behaviour of C163S mutation and C163S mutation with adjacent phosphorylation was investigated. We have examined the structural impact of phosphorylated forms and C163S mutation in AGA. Molecular dynamics simulations (200 ns) exposed patterns of deviation, fluctuation, and change in compactness of Y178 phosphorylated AGA protein (Y178-p), T215 phosphorylated AGA protein (T215-p), T324 phosphorylated AGA protein (T324-p), C163S mutant AGA protein (C163S), and C163S mutation with Y178 phosphorylated AGA protein (C163S-Y178-p). Y178-p, T215-p, and C163S mutation demonstrated an increase in intramolecular hydrogen bonds, leading to greater compactness of the AGA forms. Principle component analysis (PCA) and Gibbs free energy of the phosphorylated/C163S mutation structures exhibit transition in motion/orientation than Wild type (WT). T215-p may be more dominant among these than the other studied phosphorylated forms. It might contribute to hydrolyzing L-asparagine functioning as an asparaginase, thereby regulating neurotransmitter activity. This study revealed structural insights into the phosphorylation of Y178, T215, and T324 in AGA protein. Additionally, it exposed the structural changes of the C163S mutation and C163S-Y178-p of AGA protein. This research will shed light on a better understanding of AGA's phosphorylated mechanism.Communicated by Ramaswamy H. Sarma.
Hrituraj Dey, Karthick Vasudevan, George Priya Doss C., S. Udhaya Kumar, Achraf El Allali, Alsamman M. Alsamman, and Hatem Zayed
Frontiers Media SA
IntroductionOsteosarcoma is a rare disorder among cancer, but the most frequently occurring among sarcomas in children and adolescents. It has been reported to possess the relapsing capability as well as accompanying collateral adverse effects which hinder the development process of an effective treatment plan. Using networks of omics data to identify cancer biomarkers could revolutionize the field in understanding the cancer. Cancer biomarkers and the molecular mechanisms behind it can both be understood by studying the biological networks underpinning the etiology of the disease.MethodsIn our study, we aimed to highlight the hub genes involved in gene-gene interaction network to understand their interaction and how they affect the various biological processes and signaling pathways involved in Osteosarcoma. Gene interaction network provides a comprehensive overview of functional gene analysis by providing insight into how genes cooperatively interact to elicit a response. Because gene interaction networks serve as a nexus to many biological problems, their employment of it to identify the hub genes that can serve as potential biomarkers remain widely unexplored. A dynamic framework provides a clear understanding of biological complexity and a pathway from the gene level to interaction networks.ResultsOur study revealed various hub genes viz. TP53, CCND1, CDK4, STAT3, and VEGFA by analyzing various topological parameters of the network, such as highest number of interactions, average shortest path length, high cluster density, etc. Their involvement in key signaling pathways, such as the FOXM1 transcription factor network, FAK-mediated signaling events, and the ATM pathway, makes them significant candidates for studying the disease. The study also highlighted significant enrichment in GO terms (Biological Processes, Molecular Function, and Cellular Processes), such as cell cycle signal transduction, cell communication, kinase binding, transcription factor activity, nucleoplasm, PML body, nuclear body, etc.ConclusionTo develop better therapeutics, a specific approach toward the disease targeting the hub genes involved in various signaling pathways must have opted to unravel the complexity of the disease. Our study has highlighted the candidate hub genes viz. TP53, CCND1 CDK4, STAT3, VEGFA. Their involvement in the major signaling pathways of Osteosarcoma makes them potential candidates to be targeted for drug development. The highly enriched signaling pathways include FOXM1 transcription pathway, ATM signal-ling pathway, FAK mediated signaling events, Arf6 signaling events, mTOR signaling pathway, and Integrin family cell surface interactions. Targeting the hub genes and their associated functional partners which we have reported in our studies may be efficacious in developing novel therapeutic targets.
Ambritha Balasundaram, Udhaya Kumar. S, Thirumal Kumar. D, Aditi Anil Dedge, Gnanasambandan. R, Satish Srinivas. K, Siva R, and George Priya Doss C
Informa UK Limited
Breast cancer biomarkers that detect marginally advanced stages are still challenging. The detection of specific abnormalities, targeted therapy selection, prognosis, and monitoring of treatment effectiveness over time are all made possible by circulating free DNA (cfDNA) analysis. The proposed study will detect specific genetic abnormalities from the plasma cfDNA of a female breast cancer patient by sequencing a cancer-related gene panel (MGM455 - Oncotrack Ultima), including 56 theranostic genes (SNVs and small INDELs). Initially, we determined the pathogenicity of the observed mutations using PredictSNP, iStable, Align-GVGD, and ConSurf servers. As a next step, molecular dynamics (MD) was implemented to determine the functional significance of SMAD4 mutation (V465M). Lastly, the mutant gene relationships were examined using the Cytoscape plug-in GeneMANIA. Using ClueGO, we determined the gene's functional enrichment and integrative analysis. The structural characteristics of SMAD4 V465M protein by MD simulation analysis further demonstrated that the mutation was deleterious. The simulation showed that the native structure was more significantly altered by the SMAD4 (V465M) mutation. Our findings suggest that SMAD4 V465M mutation might be significantly associated with breast cancer, and other patient-found mutations (AKT1-E17K and TP53-R175H) are synergistically involved in the process of SMAD4 translocate to nuclease, which affects the target gene translation. Therefore, this combination of gene mutations could alter the TGF-β signaling pathway in BC. We further proposed that the SMAD4 protein loss may contribute to an aggressive phenotype by inhibiting the TGF-β signaling pathway. Thus, breast cancer's SMAD4 (V465M) mutation might increase their invasive and metastatic capabilities.Communicated by Ramaswamy H. Sarma.
N. Madhana Priya, Ambritha Balasundaram, N. Sidharth Kumar, S. Udhaya Kumar, D. Thirumal Kumar, R. Magesh, Hatem Zayed, and C. George Priya Doss
Elsevier
Ankur Datta, Hephzibah Cathryn R., S. Udhaya Kumar, Karthick Vasudevan, D. Thirumal Kumar, Hatem Zayed, and C. George Priya Doss
Elsevier
Ankur Datta, S. Udhaya Kumar, Maria D'costa, Anusha Bothe, D. Thirumal Kumar, Hatem Zayed, and C. George Priya Doss
Elsevier
D. John Dickson Calvin, Runal John Steve, Rajesh Kannangai, Priya Abraham, S. Udhaya Kumar, Ambritha Balasundaram, C. George Priya Doss, Vinotha Thomas, Anitha Thomas, Debashish Danda,et al.
Informa UK Limited
Epidemiological link between HPV and SLE is evolving. The possibility of HPV infection-induced molecular mimicry and systemic lupus erythematosus (SLE) was elucidated through detailed in silico analyses. Conserved regions in the structural protein sequences of high-risk HPV types were inferred, and sequence homologies between viral and human peptides were identified to delineate proteins implicated in SLE. B-cell epitopes and MHC-class II binding were compiled using Immune Epitope Database and ProPred II analysis tool. Molecular modeling and molecular dynamics/simulation (MDS) were performed using AutoDock Vina and GROMACS, respectively. Sequence alignment revealed 32 conserved regions, and 27/32 viral peptides showed varying similarities to human peptides, rich in B-cell epitopes with superior accessibility, high hydrophilicity, antigenicity and disposition to bind many class-II HLA alleles. Molecular docking of 13 viral peptides homologous (100%) to human peptides implicated in SLE showed that VIR-PEP1 (QLFNKPYWL) and VIR-PEP2 (DTYRFVTS) exhibited higher binding affinities than corresponding human peptides to SLE predisposing HLA-DRB1 allele. MDS of these peptides showed that the viral peptides had superior folding, compactness, and a higher number of hydrogen bonds than human peptides throughout the simulation period. SASA analysis revealed that the VIR-PEP1&2 fluctuated less frequently than corresponding human peptides. MM-PBSA revealed that the VIR-PEP2 complex exhibited higher binding energy than the human peptide complex. This suggests that highly conserved structural peptides of high-risk HPV types homologous to human peptides could compete and bind avidly to the HLA allele associated with SLE and predispose HPV-infected individuals to SLE through molecular mimicry.Communicated by Ramaswamy H. Sarma.
Nilmani, Maria D'costa, Anusha Bothe, Soumik Das, S. Udhaya Kumar, R. Gnanasambandan, and C. George Priya Doss
Elsevier
Keerthana G., Karthick Vasudevan, Hrituraj Dey, Tasmia Kausar, S. Udhaya Kumar, D. Thirumal Kumar, Hatem Zayed, and C. George Priya Doss
Elsevier
Karthick Vasudevan, S. Udhaya Kumar, A. Mithun, B. Raghavendra, and C. George Priya Doss
Elsevier
Heba Almaghrbi, Rehab Elkardawy, S. Udhaya Kumar, Shilpa Kuttikrishnan, Taghreed Abunada, Manoj Kumar Kashyap, Aamir Ahmad, Shahab Uddin, C. George Priya Doss, and Hatem Zayed
Elsevier
Leepica Kapoor, S. Udhaya Kumar, Sourav De, Sujithra Vijayakumar, Nitin Kapoor, S. K. Ashok Kumar, George Priya Doss C, and Siva Ramamoorthy
Royal Society of Chemistry (RSC)
Inhibitory potential of plant pigment bixin against UVA induced activation of dermal enzymic pathway related photo skin aging.
Udhaya Kumar S, Ambritha Balasundaram, Hephzibah Cathryn R, Rinku Polachirakkal Varghese, Siva R, Gnanasambandan R, Salma Younes, Hatem Zayed, and George Priya Doss C
Elsevier BV
N. Madhana Priya, S. Udhaya Kumar, D. Thirumal Kumar, R. Magesh, R. Siva, R. Gnanasambandan, and C. George Priya Doss
Elsevier
D. Thirumal Kumar, Nishaat Shaikh, S. Udhaya Kumar, and C. George Priya Doss
Elsevier
Iftikhar A. Tayubi, Udhaya Kumar S., and George Priya Doss C.
Wiley
AbstractThe mutations at the hotspot region of K‐Ras result in the progression of cancer types. Our study aimed to explore the small molecule inhibitors against the G13D mutant K‐Ras model with anti‐cancerous activity from food and drug administration (FDA)‐approved drug compounds. We implemented several computational strategies such as pharmacophore‐based virtual screening, molecular docking, absorption, distribution, metabolism and excretion features, and molecular simulation to ensure the identified hit compounds have potential efficacy against G13D K‐Ras. We found that the FDA‐approved compounds, namely, azelastine, dihydrocodeine, paroxetine, and tramadol, are potential candidates to inhibit the action of G13D mutant K‐Ras. All four compounds exhibited similar binding patterns of sotorasib, and a structural binding mechanism with significant hydrophobic contacts. The descriptor features from the QikProp of all four compounds are within allowable limits compared to sotorasib drug. Consequently, a molecular simulation result emphasized that the dihydrocodeine and tramadol exhibited less fluctuation, minimal basin, significant h‐bonds, and potent inhibition against G13D K‐Ras. As a result, the current research identifies prospective K‐Ras inhibitors that could be further improved with biochemical analysis for precision medicine against K‐Ras‐driven cancers.