Publications by authors named "Karthikeyan Muthusamy"

56 Publications

Structural and functional insights on vitamin D receptor and CYP24A1 deleterious single nucleotide polymorphisms: A computational and pharmacogenomics perpetual approach.

Cell Biochem Funct 2021 Jul 6. Epub 2021 Jul 6.

Department of Bioinformatics, Alagappa University, Karaikudi, India.

The development of chronic kidney disease (CKD) drugs remains a challenge due to the variations in the genes. The vitamin D receptor (VDR) and Cytochrome 24A1 (CYP24A1) genetic variants might affect the drug potency, efficacy and pathway. Here we have to analyse and determine the deleterious single-nucleotide polymorphisms (nsSNPs) of VDR and CYP24A1 genes and their different population's drug responses in different populations to understand the key role in CKD. Among that the large scale of nsSNP, we used certain computational tools that predicted six missense variants are observed to be significantly damaging effect and SNP variability with large differences in various populations. Molecular docking studies were carried out by clinical and our screened compounds to VDR and CYP24A1. Docking results revealed all the compounds have a good binding affinity (Score). The screened compounds (TCM_2868 and UNPD_141613) show good binding affinity when compared to known compounds. The QM/MM study revealed that the compounds have electron transfer ability and act as a donor/acceptor to mutated proteins. The structural and conformational changes of protein complexes were analysed by molecular dynamics study. Hence, this study helps to identify suitable drugs through drug discovery in CKD treatment. The abovementioned compounds have more binding affinity, efficacy, and potency of both wild and mutant of VDR and CYP24A1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbf.3658DOI Listing
July 2021

Mechanistic insights on nsSNPs on binding site of renin and cytochrome P450 proteins: A computational perceptual study for pharmacogenomics evaluation.

J Cell Biochem 2021 Jun 23. Epub 2021 Jun 23.

Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India.

Past several decades, therapeutic investigations lead to the discovery of numerous antihypertensive drugs. Although it has been proved for their potency, altered efficacy is common norms in several conditions due to genetic variations. Cytochrome P450 plays a crucial role in drug metabolism and responsible for the pharmacokinetic and pharmacodynamic properties of the drug molecules. Here, we report the deleterious point mutations in the genes associated with the altered response of antihypertensive drug molecules and their metabolizers. Missense variants were filtered as potential nonsynonymous single nucleotide polymorphisms among the available data for the target genes (REN, CYP2D6, CYP3A4). The key objective of the work is to identify the deleterious single nucleotide polymorphisms (SNPs) responsible for the drug response and metabolism for the application of personalized medication. The molecular docking studies revealed that Aliskiren and other clinically approved drug molecules have a high binding affinity with both wild and mutant structures of renin, CYP2D6, and CYP3A4 proteins. The docking (Glide XP) score was observed to have in the range of -8.896 to -11.693 kcal/mol. The molecular dynamics simulation studies were employed to perceive the structural changes and conformational deviation through various analyses. Each studied SNPs was observed to have disparate scoring in the binding affinity to the specific drug molecules. As a prospective plan, we assume this study might be applied to identify the risky SNPs associated with hypertension from the patients to recommend the suitable drug for personalized hypertensive treatment. Further, extensive clinical pharmacogenomics studies are required to support the findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.30069DOI Listing
June 2021

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

Exp Biol Med (Maywood) 2021 Mar 27:15353702211002181. Epub 2021 Mar 27.

Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA 92357, USA.

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. molecular docking and high-throughput virtual screening on zinc database identified seven compounds predicted to bind to an active site within the βC'-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 . Anti-FGFR3 treatment completely blocked the stimulatory effect of 14977614 on BMSC proliferation. 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 studies showed that compound 14977614 exerts significant biological effects on osteogenic cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/15353702211002181DOI Listing
March 2021

Corrigendum: Global Text Mining and Development of Pharmacogenomic Knowledge Resource for Precision Medicine.

Front Pharmacol 2020 4;11:614445. Epub 2020 Dec 4.

Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR)-Institute of Genomics and Integrative Biology (IGIB), New Delhi, India.

[This corrects the article DOI: 10.3389/fphar.2019.00839.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.614445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746840PMC
December 2020

TRAF2 and NCK-Interacting Kinase Inhibitors for Colorectal Cancer: In Vitro and Theoretical Validations.

ACS Comb Sci 2020 11 29;22(11):608-616. Epub 2020 Sep 29.

Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore-632014, India.

TRAF2 and NCK-interacting kinase (TNIK) is a critical factor in colorectal cancer (CRC) proliferation mediated by signaling. We attempted to identify efficient TNIK inhibitors using computational high-throughput virtual screening (HTVS) from various drug banks and databases. By performing/on performing e-pharmacophore screening and molecular docking methods, from ∼700 000 molecules, compounds LC_222150, LC_112060, and LC_64796 were identified as potential leads, through molecular dynamics (MD) simulations and density functional theory (DFT). These top 3 structures were commercially procured, and their inhibitory activity was assessed in vitro. Significant TNIK inhibition was observed, with an average IC of 18.33 ± 0.75 nM. In terms of anticancer activity, the observed average relative % activity (RPA) of 90.28 ± 1.04 for these compounds compared well with doxorubicin (86.75 ± 1.45) as a standard. Compounds LC_222150, LC_112060, and LC_64796, therefore, warrant further evaluation in vivo to assess their CRC therapeutic effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acscombsci.0c00027DOI Listing
November 2020

Structural insights on vitamin D receptor and screening of new potent agonist molecules: structure and ligand-based approach.

J Biomol Struct Dyn 2021 Jul 11;39(11):4148-4159. Epub 2020 Jun 11.

Department of Bioinformatics, Alagappa University, Karaikudi, India.

Vitamin D deficiency is one of the common clinical symptoms of severe chronic kidney disease (CKD) patients. Vitamin D receptor (VDR) is a part of the nuclear receptor family exerts vitamin D activation to maintain calcium/phosphorous homeostasis and bone metabolism. The reduction of VDR activity leads to vitamin D deficiency. In this study, we found three potent agonists for VDR protein on the structure and ligand-based screening methods. In the structure-based method, 792 compounds were screened. A 5-point pharmacophore (one hydrogen bond acceptor, two hydrophobic and aromatic rings (AHHRR)) was developed and used to obtain a predictive 3 D-Quantitative structure-activity relationship (QSAR), model. The acquire R and Q values are 0.8676 and 0.8523 respectively. Further, E-pharmacophore based screening, molecular docking (binding affinity), Molecular Mechanics-Generalized Born Surface Area (binding free energy), chemical reactivity (Density Functional Theory (DFT) study) and molecular dynamics (protein-ligand stability) analysis were done. Hence, the computational investigations demonstrate that the identified ligands such as TCM_1875, TCM_1874, and TCM_2868 showed promising agonist effect on VDR protein. Further validation and experiments need to be done to confirm the potency of the identified compounds shortly.Communicated by Ramaswamy H. Sarma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2020.1775122DOI Listing
July 2021

Computational study on cross-talking cancer signalling mechanism of ring finger protein 146, AXIN and Tankyrase protein complex.

J Biomol Struct Dyn 2020 Oct 2;38(17):5173-5185. Epub 2019 Dec 2.

Department of Bioinformatics, Alagappa University, Karaikudi, Tamilnadu, India.

Cancer is distinguished by uncontrolled cell growth and it is regulated by several environmental and genetic factors. The Wnt β-Catenin signaling pathway has been considered as the most significant colon cancer-targeted pathway. AXIN plays a major regulatory role in the Wnt signaling mechanism. The AXIN after PARsylated by TNKS is ubiqutinated by RNF146 through its WWE domain that leads to degradation of AXIN protein. Several studies have been proposed highlighting the inhibition of the PARsylation mechanism that mediates the degradation of AXIN and improves β-catenin stability. The present study focused on the identification of potential inhibitors for the inhibition of RNF146-TNKS complex through identifying potential RNF146 inhibitors to prevent ubiquitination of AXIN, further to confirm the regulatory role and inhibition mechanism of RNF146-AXIN and RNF146-TNKS. The docked complex was then evaluated using various computational analysis. Molecular interactions analysis was performed to observe the interacting residues between the protein complex. The compounds from various databases were docked with the RNF146 and complex proteins. Both the protein complex and ligand were analyzed for the confirmation of structural stability using molecular dynamics simulations. Selected compounds' atomic configuration and electron profile were analyzed through DFT calculations and ADME/T (Physico-chemical) properties. As a result, we found several common lead compounds for RNF146, TNKS protein inhibition. Therefore, the docked compounds may act as a better antagonist molecule for RNF146, TNKS and associated signaling molecules. Further, experimental validations are required to prove the potency of the identified compounds.Communicated by Ramaswamy H. Sarma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2019.1696707DOI Listing
October 2020

Tannic acid prevents macrophage-induced pro-fibrotic response in lung epithelial cells via suppressing TLR4-mediated macrophage polarization.

Inflamm Res 2019 Dec 5;68(12):1011-1024. Epub 2019 Sep 5.

Department of Biotechnology, BIT-Campus, Anna University, Tiruchirappalli, Tamil Nadu, India.

Background: Polarized macrophages induce fibrosis through multiple mechanisms, including a process termed epithelial-to-mesenchymal transition (EMT). Mesenchymal cells contribute to the excessive accumulation of fibrous connective tissues, leading to organ failure. This study was aimed to investigate the effect of tannic acid (TA), a natural dietary polyphenol on M1 macrophage-induced EMT and its underlying mechanisms.

Materials: First, we induced M1 polarization in macrophage cell lines (RAW 264.7 and THP-1). Then, the conditioned-medium (CM) from these polarized macrophages was used to induce EMT in the human adenocarcinomic alveolar epithelial (A549) cells. We also analysed the role of TA on macrophage polarization.

Results: We found that TA pre-treated CM did not induce EMT in epithelial cells. Further, TA pre-treated CM showed diminished activation of MAPK in epithelial cells. Subsequently, TA was shown to inhibit LPS-induced M1 polarization in macrophages by directly targeting toll-like receptor 4 (TLR4), thereby repressing LPS binding to TLR4/MD2 complex and subsequent signal transduction.

Conclusion: It was concluded that TA prevented M1 macrophage-induced EMT by suppressing the macrophage polarization possibly through inhibiting the formation of LPS-TLR4/MD2 complex and blockage of subsequent downstream signal activation. Further, our findings may provide beneficial information to develop new therapeutic strategies against chronic inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00011-019-01282-4DOI Listing
December 2019

Global Text Mining and Development of Pharmacogenomic Knowledge Resource for Precision Medicine.

Front Pharmacol 2019 7;10:839. Epub 2019 Aug 7.

Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR)-Institute of Genomics and Integrative Biology (IGIB), New Delhi, India.

Understanding patients' genomic variations and their effect in protecting or predisposing them to drug response phenotypes is important for providing personalized healthcare. Several studies have manually curated such genotype-phenotype relationships into organized databases from clinical trial data or published literature. However, there are no text mining tools available to extract high-accuracy information from such existing knowledge. In this work, we used a semiautomated text mining approach to retrieve a complete pharmacogenomic (PGx) resource integrating disease-drug-gene-polymorphism relationships to derive a global perspective for ease in therapeutic approaches. We used an R package, pubmed.mineR, to automatically retrieve PGx-related literature. We identified 1,753 disease types, and 666 drugs, associated with 4,132 genes and 33,942 polymorphisms collated from 180,088 publications. With further manual curation, we obtained a total of 2,304 PGx relationships. We evaluated our approach by performance (precision = 0.806) with benchmark datasets like Pharmacogenomic Knowledgebase (PharmGKB) (0.904), Online Mendelian Inheritance in Man (OMIM) (0.600), and The Comparative Toxicogenomics Database (CTD) (0.729). We validated our study by comparing our results with 362 commercially used the US- Food and drug administration (FDA)-approved drug labeling biomarkers. Of the 2,304 PGx relationships identified, 127 belonged to the FDA list of 362 approved pharmacogenomic markers, indicating that our semiautomated text mining approach may reveal significant PGx information with markers for drug response prediction. In addition, it is a scalable and state-of-art approach in curation for PGx clinical utility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.00839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692532PMC
August 2019

Author Correction: Overcoming NADPH product inhibition improves D-sorbitol conversion to L-sorbose.

Sci Rep 2019 Aug 15;9(1):12096. Epub 2019 Aug 15.

Department of Chemical Engineering, Konkuk University, 1 Hwayang-Dong, Gwangjin-Gu, Seoul, 05029, Republic of Korea.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-48082-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695483PMC
August 2019

Computational and Pharmacogenomic Insights on Hypertension Treatment: Rational Drug Design and Optimization Strategies.

Curr Drug Targets 2020 ;21(1):18-33

Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India.

Background: Hypertension is a prevalent cardiovascular complication caused by genetic and nongenetic factors. Blood pressure (BP) management is difficult because most patients become resistant to monotherapy soon after treatment initiation. Although many antihypertensive drugs are available, some patients do not respond to multiple drugs. Identification of personalized antihypertensive treatments is a key for better BP management.

Objective: This review aimed to elucidate aspects of rational drug design and other methods to develop better hypertension management.

Results: Among hypertension-related signaling mechanisms, the renin-angiotensin-aldosterone system is the leading genetic target for hypertension treatment. Identifying a single drug that acts on multiple targets is an emerging strategy for hypertension treatment, and could be achieved by discovering new drug targets with less mutated and highly conserved regions. Extending pharmacogenomics research to include patients with hypertension receiving multiple antihypertensive drugs could help identify the genetic markers of hypertension. However, available evidence on the role of pharmacogenomics in hypertension is limited and primarily focused on candidate genes. Studies on hypertension pharmacogenomics aim to identify the genetic causes of response variations to antihypertensive drugs. Genetic association studies have identified single nucleotide polymorphisms affecting drug responses. To understand how genetic traits alter drug responses, computational screening of mutagenesis can be utilized to observe drug response variations at the protein level, which can help identify new inhibitors and drug targets to manage hypertension.

Conclusion: Rational drug design facilitates the discovery and design of potent inhibitors. However, further research and clinical validation are required before novel inhibitors can be clinically used as antihypertensive therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389450120666190808101356DOI Listing
February 2021

Overcoming NADPH product inhibition improves D-sorbitol conversion to L-sorbose.

Sci Rep 2019 01 28;9(1):815. Epub 2019 Jan 28.

Department of Chemical Engineering, Konkuk University, 1 Hwayang-Dong, Gwangjin-Gu, Seoul, 05029, Republic of Korea.

Gluconobacter oxydans sorbitol dehydrogenase (GoSLDH) exhibits a higher catalytic efficiency than other L-sorbose producing enzymes. During the reaction catalysed by GoSLDH, NADP is reduced to NADPH and D-sorbitol is oxidized to L-sorbose. However, GoSLDH activity is inhibited by the NADPH (K = 100 μM) formed during the enzymatic reaction. Therefore, Escherichia coli producing both GoSLDH for D-sorbitol oxidation and LreNOX (NAD(P)H oxidase from Lactobacillus reuteri) for NADP regeneration was generated and used for L-sorbose production. Whole cell biocatalysts with the LreNOX cofactor recycling system showed a high conversion rate (92%) of D-sorbitol to L-sorbose in the presence of low concentration of NADP (0.5 mM). By alleviating NADPH accumulation during the catalytic reactions, E. coli exhibited 23-fold higher conversion rate of D-sorbitol than E. coli. L-Sorbose production by E. coli reached 4.1 g/L after 40 min, which was 20.5-fold higher than that of E. coli. We also constructed G. oxydans and G. oxydans strains, and they exhibited 1.2- and 2.9-fold higher conversion rates than the wild-type G. oxydans KCTC 1091. The results indicate that overcoming NADPH product inhibition using LreNOX improves chemical production in NADP-dependent enzymatic reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-37401-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349845PMC
January 2019

Inhibitory potential of Hydroxychavicol on Ehrlich ascites carcinoma model and interaction on cancer targets.

Nat Prod Res 2020 Jun 23;34(11):1591-1596. Epub 2018 Nov 23.

Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.

Hydroxychavicol (HC), a major phenolic derivative isolated from the leaves of is well known for its antibacterial, antifungal and antimutagenic properties. The present study evaluated the antitumor activity of HC against Ehrlich Ascites Carcinoma (EAC) cells in Swiss albino mice and interaction of HC with the receptors involved in the cancer. Hydroxychavicol (200 and 400 mg/kg bw) was orally administered for 21 consecutive days and was effective in inhibiting the tumor growth in ascitic mouse model. HC consistently reduced the tumor volume, viable cell count, lipid peroxidation and elevated the life span of HC treated mice. Besides the hematological profiles, SGOT and SGPT levels reverted back to normal and oxidative stress markers GSH, SOD and CAT also increased in HC treated groups. docking analysis revealed that HC possessed potent antagonist activity against all the cancer targets demonstrating its inhibitory activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14786419.2018.1519819DOI Listing
June 2020

Current Scenario in Structure and Ligand-Based Drug Design on Anti-colon Cancer Drugs.

Curr Pharm Des 2018 ;24(32):3829-3841

Department of Bioinformatics, Faculty and Science, Alagappa University, Karaikudi, Tamil Nadu, India.

Worldwide, colorectal cancer takes up the third position in commonly detected cancer and fourth in cancer mortality. Recent progress in molecular modeling studies has led to significant success in drug discovery using structure and ligand-based methods. This study highlights aspects of the anticancer drug design. The structure and ligand-based drug design are discussed to investigate the molecular and quantum mechanics in anti-cancer drugs. Recent advances in anticancer agent identification driven by structural and molecular insights are presented. As a result, the recent advances in the field and the current scenario in drug designing of cancer drugs are discussed. This review provides information on how cancer drugs were formulated and identified using computational power by the drug discovery society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1381612824666181114114513DOI Listing
December 2019

A theoretical insight to understand the molecular mechanism of dual target ligand CTA-018 in the chronic kidney disease pathogenesis.

PLoS One 2018 4;13(10):e0203194. Epub 2018 Oct 4.

Department of Bioinformatics, Alagappa University, Karaikudi, India.

The level of the vitamin D in the bloodstream is regulated by cytochrome P450 enzyme 24-hydroxylase A1 (CYP24A1). Over expression of CYP24A1 enzyme is correlated with vitamin D deficiency and resistance to vitamin D therapy. Chronic kidney disease (CKD) patients are commonly reported with the above said expression variations. This deregulation could be solved by ligands that act as a vitamin D receptor (VDR) agonists and CYP24A1 antagonists. Posner et al., (2010) first time reported two new vitamin D analogues namely CTA-091 and CTA-018 to inhibit CYP24A1. The CTA-018 inhibited CYP24A1 with an IC50 27 ± 6 nM (10 times more potent than the ketoconazole (253 ± 20 nM)). CTA-018 induced VDR expression (15-fold lower than 1α,25(OH)2D3) and is under phase II clinical trial, whereas CTA-091 was not able to efficiently induce the VDR expression (>2000 nM). To explore the molecular mechanism, binding specificity of these two vitamin D analogues along with native ligand was extensively studied through in silico approaches. Through molecular dynamics simulations studies, we shown that the sulfonic group (O = S = O) in the side chain of CTA-018 plays an important role in the regulation of VDR agonistic activity. The electron lone pairs of the sulfonic group that interacted with His393 lead to be a factor for agonistic mechanism of VDR activity. Compared to azol-based compounds, CTA-018 binds the different sites in the CYP24A1 binding cavity and thus it could be a potent antagonistic for CYP24A1enzyme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171836PMC
March 2019

insights on tankyrase protein: A potential target for colorectal cancer.

J Biomol Struct Dyn 2019 09 8;37(14):3637-3648. Epub 2018 Dec 8.

a Department of Bioinformatics , Alagappa University , Karaikudi , India.

The Wnt/β-catenin pathway plays an important regulatory role in cancer signaling and cell regenerative mechanisms. Its suppression has long been considered as an important challenge of anticancer treatment and management. The poly(ADP-ribose) polymerase (PARP) family represented as a new class of therapeutic targets with diverse potential disease indications. Tankyrase (TNKS) is considered to be a potential target for the intervention of various cancers. The main objective of the work is to explore the molecular and quantum mechanics of the drug-like compounds and to identify the potential inhibitors for TNKS protein using the structure and ligand-based virtual screening from several databases and to explore the binding pocket and interactions of active residues. The screened compounds were further filtered using binding-free energy calculation and molecular dynamics simulation studies. The results have provided a strong molecular knowledge of TNKS and offered top hit potent inhibitors. The identified lead compounds LC_40781, LC_40777, LC_39767, LC_8346, NCI_682438, and NCI_721141 were observed to have potent activity against TNKS protein. The hydrogen bonding of compounds with Asp1198, His1201, Tyr1203 in TNKS1 and Gly1032, Ser1068 in TNKS2 are the key interactions plays a major role in binding energy. Therefore, the outcome of the study would help for further validation and provides valuable information to guide the future TNKS-specific inhibitor designing. Communicated by Ramaswamy H. Sarma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2018.1521748DOI Listing
September 2019

Atom-based and Pharmacophore-based 3D - QSAR Studies on Vitamin D Receptor (VDR).

Comb Chem High Throughput Screen 2018 ;21(5):329-343

Deparment of Bioinformatics, Alagappa University, Karaikudi 630 004, Tamil Nadu, India.

Aim And Objective: Vitamin D3 (1,25(OH)2D3) is a biologically active metabolite and plays a wide variety of regulatory functions in human systems. Currently, several Vitamin D analogues have been synthesized and tested against VDR (Vitamin D Receptor). Electrostatic potential methods are greatly influence the structure-based drug discovery. In this study, ab inito (DFT, HF, LMP2) and semi-empirical (RM1, AM1, PM3, MNDO, MNDO/d) charges were examined on the basis of their concert in predicting the docking pose using Induced Fit Docking (IFD) and binding free energy calculations against the VDR.

Materials And Methods: Initially, we applied ab initio and semi-empirical charges to the 38 vitamin D analogues. Further, the charged analogues have been docked in the VDR active site. We generated the structure-based 3D-QSAR from the docked conformation of vitamin D analogues. On the other hand, we performed pharmacophore-based 3D-QSAR.

Results: The result shows that, AM1 is the good charge model for our study and AM1 charge based QSAR produced more accurate ligand poses. Furthermore, the hydroxyl group in the side chain of vitamin D analogues played an important role in the VDR antagonistic activity.

Conclusion: Overall, we found that charge-based optimizations of ligands were out performed than the pharmacophore based QSAR model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1386207321666180607101720DOI Listing
December 2019

In silico identification and screening of CYP24A1 inhibitors: 3D QSAR pharmacophore mapping and molecular dynamics analysis.

J Biomol Struct Dyn 2019 Apr 4;37(7):1700-1714. Epub 2018 May 4.

a Department of Bioinformatics , Alagappa University , Karaikudi , Tamilnadu , India.

Vitamin D is a key signalling molecule that plays a vital role in the regulation of calcium phosphate homeostasis and bone remodelling. The circulating biologically active form of vitamin D is regulated by the catabolic mechanism of cytochrome P450 24-hydroxylase (CYP24A1) enzyme. The over-expression of CYP24A1 negatively regulates the vitamin D level, which is the causative agent of chronic kidney disease, osteoporosis and several types of cancers. In this study, we found three potential lead molecules adverse to CYP24A1 through structure-based, atom-based pharmacophore and e-pharmacophore-based screening methods. Analysis was done by bioinformatics methods and tools like binding affinity (binding free energy), chemical reactivity (DFT studies) and molecular dynamics simulation (protein-ligand stability). Combined computational investigation showed that the compounds NCI_95001, NCI_382818 and UNPD_141613 may have inhibitory effects against the CYP24A1 protein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2018.1464958DOI Listing
April 2019

Vitamin D receptor (VDR) non-synonymous single nucleotide polymorphisms (nsSNPs) affect the calcitriol drug response - A theoretical insight.

J Mol Graph Model 2018 05 12;81:14-24. Epub 2018 Feb 12.

Department of Bioinformatics, Alagappa University, Karaikudi, 630 004, India.

Pharmacogenetics and pharmacogenomics have become presumptive with advancements in next-generation sequencing technology. In complex diseases, distinguishing the feasibility of pathogenic and neutral disease-causing variants is a time consuming and expensive process. Recent drug research and development processes mainly rely on the relationship between the genotype and phenotype through Single nucleotide polymorphisms (SNPs). The SNPs play an indispensable role in elucidating the individual's vulnerability to disease and drug response. The understanding of the interplay between these leads to the establishment of personalized medicine. In order to address this issue, we developed a computational pipeline of vitamin D receptor (VDR) for SNP centered study by application of elegant molecular docking and molecular dynamics simulation approaches. In a few SNPs the volume of the binding cavities has increased in mutant structures when compared to the wild type, indicating a weakening in interaction (699.1 Å in wild type Vs. 738.8 in Leu230Val, 820.7 Å in Arg247Leu). This also differently reflected in the H-bond interactions and binding free energies -169.93 kcal/mol (wild type) Vs -156.43 kcal/mol (R154W), -105.49 kcal/mol (R274L) in Leu230Val and Arg247Leu respectively. Although we could not find noteworthy changes in the binding free energies and binding pocket in the remaining mutations, the H-bond interactions made these SNPs deleterious. Thus, we further analyzed the H-bond interactions and distances using molecular dynamics (MD) simulation studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmgm.2018.02.004DOI Listing
May 2018

Design, synthesis, and characterization of α, β-unsaturated carboxylic acid, and its urea based derivatives that explores novel epigenetic modulators in human non-small cell lung cancer A549 cell line.

J Cell Physiol 2018 07 25;233(7):5293-5309. Epub 2018 Jan 25.

Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.

Histone deacetylase inhibitors (HDACi) are a small molecule chemotherapeutics that target the chromatin remodeling through the regulation of histone and non-histone proteins. These inhibitors directed against histone deacetylase (HDAC) enzymes have become an important therapeutic tool in oncology; consequently, scientific efforts have fortified the quest for newer and novel HDACi, which forces the design of structurally innovative HDACi. Various urea containing compounds exhibited admirable anticancer activity. On the basis of these observations, we design and synthesize HDAC specific blocker molecules which are specifically besieged towards class I, class II, and class IV HDAC isoforms to enhance the structural assortment for HDACi. Through docking experiments, we identified that the compounds were tightly bound to the isoforms of the HDAC enzymes at their receptor regions. These derivatives potently inhibited the different isoforms, namely, class I, II, and IV of HDACs, by hyperacetylation of lysine residues in A549 cells. The mechanism of apoptosis is evident, regulating tumor suppressor genes and proteins, thereby facilitating the activation of the death receptor pathway by the tumor necrosis factor (TNF) receptor. These derivative facilitated the induction of reactive oxygen species (ROS) generation leading to downregulation of Bcl , and upregulation of Bax expression, thereby dysregulating mitochondrial membrane potential (ΔΨ ) to release cytochrome c, and activation of intrinsic pathway. These compounds downregulate the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway to inhibit cell growth, proliferation, and metastasis through the matrix metalloproteinases (MMPs) MMP2 and MMP9 in A549 cells. These results suggest that our designed urea based derivatives act as epigenetic targeting agents through HDAC inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.26333DOI Listing
July 2018

Computational and in vitro insights on snake venom phospholipase A inhibitor of phytocompound ikshusterol3-O-glucoside of Clematis gouriana Roxb. ex DC.

J Biomol Struct Dyn 2018 Dec 14;36(16):4197-4208. Epub 2017 Dec 14.

c Department of Biotechnology , Karpagam Academy of Higher Education (Karpagam University) , Coimbatore 641021 , Tamil Nadu , India.

Ikshusterol3-O-glucoside was isolated from Clematis gouriana Roxb. ex DC. root. A structure of the isolated compound was determined on the basis of various spectroscopic interpretations (UV, NMR, FTIR, and GC-MS-EI). This structure was submitted in the PubChem compound database (SID 249494133). SID 249494133 was carried out by density functional theory calculation to observe the chemical stability and electrostatic potential of this compound. The absorption, distribution, metabolism, and excretion property of this compound was predicted to evaluate the drug likeness and toxicity. In addition, molecular docking, quantum polarized ligand docking, prime MMGBSA calculation, and induced fit docking were performed to predict the binding status of SID 249494133 with the active site of phospholipase A (PLA) (PDB ID: 1A3D). The stability of the compound in the active site of PLA was carried out using molecular dynamics simulation. Further, the anti-venom activity of the compound was assessed using the PLA assay against Naja naja (Indian cobra) crude venom. The results strongly show that Ikshusterol3-O-glucoside has a potent snake-venom neutralizing capacity and it might be a potential molecule for the therapeutic treatment for snakebites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2017.1409653DOI Listing
December 2018

Tannic acid attenuates TGF-β1-induced epithelial-to-mesenchymal transition by effectively intervening TGF-β signaling in lung epithelial cells.

J Cell Physiol 2018 Mar 30;233(3):2513-2525. Epub 2017 Aug 30.

Department of Biotechnology, Anna University, BIT-Campus, Tiruchirappalli, Tamil Nadu, India.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and an irreversible lung disorder characterized by the accumulation of fibroblasts and myofibroblasts in the extracellular matrix. The transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) is thought to be one of the possible sources for a substantial increase in the number of fibroblasts/myofibroblasts in IPF lungs. Tannic acid (TA), a natural dietary polyphenolic compound has been shown to possess diverse pharmacological effects. However, whether TA can inhibit TGF-β1-mediated EMT in lung epithelial cells remains enigmatic. Both the human adenocarcinomic alveolar epithelial (A549) and normal bronchial epithelial (BEAS-2B) cells were treated with TGF-β1 with or without TA. Results showed that TA addition, markedly inhibited TGF-β1-induced EMT as assessed by reduced expression of N-cadherin, type-1-collagen, fibronectin, and vimentin. Furthermore, TA inhibited TGF-β1-induced cell proliferation through inducing cell cycle arrest at G0/G1 phase. TGF-β1-induced increase in the phosphorylation of Smad (Smad2 and 3), Akt as well as that of mitogen activated protein kinase (ERK1/2, JNK1/2, and p38) mediators was effectively inhibited by TA. On the other hand, TA reduced the TGF-β1-induced increase in TGF-β receptors expression. Using molecular docking approach, FTIR, HPLC and Western blot analyses, we further identified the direct binding of TA to TGF-β1. Finally, we conclude that TA might directly interact with TGF-β1, thereby repressing TGF-β signaling and subsequent EMT process in lung epithelial cells. Further animal studies are needed to clarify its potential therapeutic benefit in pulmonary fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.26127DOI Listing
March 2018

Exploring the Carbamazepine Interaction with Human Pregnane X Receptor and Effect on ABCC2 Using in Vitro and in Silico Approach.

Pharm Res 2017 Jul 21;34(7):1444-1458. Epub 2017 Apr 21.

Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, New Delhi, India.

Purpose: Over expression of ATP-binding cassette transporters is considered one of the major reasons for non-responsiveness to antiepileptic drugs. Carbamazepine (CBZ), one of first line antiepileptic drug is known to influence ABCC2 expression but its exact molecular mechanism is unknown.

Methods: We investigated the effect of CBZ on expression of ABCC2 and pregnane X receptor (PXR) in HepG2 cell line and compared with hyperforin (agonist of PXR) and ketoconazole (antagonist of PXR) through realtime PCR and western blot assay. Involvement of PXR was demonstrated through nuclear translocation and RNA interference and related effect of CBZ on ABCC2 through functional activity assay. Molecular docking and dynamic simulation approach was used to understand the interaction of CBZ with PXR.

Results: CBZ and hyperforin increased the PXR and ABCC2 expression whereas reversed when present it in combination with ketoconazole. Experiments confirmed CBZ induced ABCC2 expression is PXR dependent. Molecular dynamic (MD) simulation and in vitro experiment indicated possibility of CBZ to be PXR agonist and PXR residue Gln285 to be important for CBZ-PXR interaction.

Conclusions: CBZ alters the functional activity of ABCC2 through PXR, which in turn can interfere with therapy. Mutational analysis of residues revealed the importance of Gln285 in ligand interaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11095-017-2161-zDOI Listing
July 2017

Computational prediction of immunodominant antigenic regions & potential protective epitopes for dengue vaccination.

Indian J Med Res 2016 Oct;144(4):587-591

Department of Bioinformatics, Science Campus, Alagappa University, Karaikudi, India.

Background & Objectives: Epitope-based vaccines (EVs) are specific, safe and easy to produce. However, vaccine failure has been frequently reported due to variation within epitopic regions. Therefore, development of vaccines based on conserved epitopes may prevent such vaccine failure. This study was undertaken to identify highly conserved antigenic regions in the four dengue serotypes to produce an epitope-based dengue vaccine.

Methods: Polyprotein sequences of all four dengue serotypes were collected and aligned using MAFFT multiple sequence alignment plugin with Geneious Pro v6.1. Consensus sequences of the polyproteins for all four dengue serotypes were designed and screened against experimentally proven epitopes to predict potential antigenic regions that are conserved among all four dengue serotypes.

Results: The antigenic region VDRGWGNGCGLFGKG was 100 per cent conserved in the consensus polyprotein sequences of all four dengue serotypes. Fifteen experimentally proven epitopes were identical to the immunodominant antigenic region.

Interpretation & Conclusions: Computationally predicted antigenic regions may be considered for use in the development of EVs for protection against dengue virus. Such vaccines would be expected to provide protection against dengue infections caused by all dengue serotypes because these would contain antigenic regions highly conserved across those serotypes. Therefore, the immunodominant antigenic region (VDRGWGNGCGLFGKG) and 15 potential epitopes may be considered for use in dengue vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0971-5916.200894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345306PMC
October 2016

Plant Isoquinoline Alkaloid Berberine Exhibits Chromatin Remodeling by Modulation of Histone Deacetylase To Induce Growth Arrest and Apoptosis in the A549 Cell Line.

J Agric Food Chem 2016 Dec 12;64(50):9542-9550. Epub 2016 Dec 12.

Department of Biochemistry, School of Life Sciences, Bharathidasan University , Tiruchirappalli, Tamil Nadu 620 024, India.

Histone deacetylases (HDACs) are a group of epigenetic enzymes that control gene expression through their repressive influence on histone deacetylation transcription. HDACs are probable therapeutic targets for cancer treatment, spurring the progress of different types of HDAC inhibitors. Further, natural-source-based derived bioactive compounds possess HDAC inhibitor property. In this way, we hypothesized that plant isoquinoline alkaloid berberine (BBR) could be a HDAC inhibitor in the human lung cancer A549 cell line. BBR represses total HDAC and also class I, II, and IV HDAC activity through hyperacetylation of histones. Furthermore, BBR triggers positive regulation of the sub-G/G cell cycle progression phase in A549 cells. Moreover, BBR-induced A549 cell growth arrest and morphological changes were confirmed using different fluorescence-dye-based microscope techniques. Additionally, BBR downregulates oncogenes (TNF-α, COX-2, MMP-2, and MMP-9) and upregulates tumor suppressor genes (p21 and p53) mRNA and protein expressions. Besides, BBR actively regulates Bcl-2/Bax family proteins and also triggered the caspase cascade apoptotic pathway in A549 cells. Our finding suggests that BBR mediates epigenetic reprogramming by HDAC inhibition, which may be the key mechanism for its antineoplastic activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jafc.6b04453DOI Listing
December 2016

Putative membrane lytic sites of P-type and S-type cardiotoxins from snake venoms as probed by all-atom molecular dynamics simulations.

J Mol Model 2016 Oct 15;22(10):238. Epub 2016 Sep 15.

Structural Biology Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur, 613 401, Tamil Nadu, India.

Cardiotoxins (CTXs) belonging to the three-finger toxin superfamily of snake venoms are one of principal toxic components and the protein toxins exhibit membrane lytic activities when the venoms are injected into victims. In the present study, complex formations between CTX VI (a P-type CTX from Naja atra) and CTX1 (an S-type CTX from Naja naja) on zwitterionic POPC bilayers (a major lipid component of cell membranes) have been studied in near physiological conditions for a total dynamic time scale of 1.35 μs using all-atom molecular dynamics (MD) simulations. Comprehensive analyses of the MD data revealed that residues such as Leu1, Lys2, Tyr11, Lys31, Asp57 and Arg58 of CTX VI, and Ala16, Lys30 and Arg58 of CTX1 were crucial for establishing interactions with the POPC bilayer. Moreover, loop I, along with globular head and loop II of CTX VI, and loop II of CTX1 were found to be the structural regions chiefly governing complex formation of the respective proteins with POPC. Rationalizations for the differential binding modes of CTXs and implications of the findings for designing small molecular inhibitors to the toxins are also discussed. Graphical Abstract Binding modes of a P-type CTX and an S-type CTX towards the POPC bilayer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00894-016-3113-yDOI Listing
October 2016

Isolation and characterization of bioactive compounds of Clematis gouriana Roxb. ex DC against snake venom phospholipase A (PLA) computational and in vitro insights.

J Biomol Struct Dyn 2017 Jul 28;35(9):1936-1949. Epub 2016 Sep 28.

d Faculty of Medicine, Department of Microbiology and Immunology , Misurata University , Misrata , Libya.

Bioactive compounds were isolated from Clematis gouriana Roxb. ex DC. The compounds were separated, characterized, the structures elucidated and submitted to the PubChem Database. The PubChem Ids SID 249494134 and SID 249494135 were tested against phospholipases A (PLA) of Naja naja (Indian cobra) venom for PLA activity. Both the compounds showed promising inhibitory activity; computational data also substantiated the results. The two compounds underwent density functional theory calculation to observe the chemical stability and electrostatic potential profile. Molecular interactions between the compounds and PLA were observed at the binding pocket of the PLA protein. Further, this protein-ligand complexes were simulated for a timescale of 100 ns of molecular dynamics simulation. Experimental and computational results showed significant PLA inhibition activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2016.1202862DOI Listing
July 2017

Combined sequence and sequence-structure based methods for analyzing FGF23, CYP24A1 and VDR genes.

Meta Gene 2016 Sep 31;9:26-36. Epub 2016 Mar 31.

Department of Bioinformatics, Alagappa University, Karaikudi 630 004, Tamilnadu, India.

FGF23, CYP24A1 and VDR altogether play a significant role in genetic susceptibility to chronic kidney disease (CKD). Identification of possible causative mutations may serve as therapeutic targets and diagnostic markers for CKD. Thus, we adopted both sequence and sequence-structure based SNP analysis algorithm in order to overcome the limitations of both methods. We explore the functional significance towards the prediction of risky SNPs associated with CKD. We assessed the performance of four widely used pathogenicity prediction methods. We compared the performances of the programs using Mathews correlation Coefficient ranged from poor (MCC = 0.39) to reasonably good (MCC = 0.42). However, we got the best results for the combined sequence and structure based analysis method (MCC = 0.45). 4 SNPs from FGF23 gene, 8 SNPs from VDR gene and 13 SNPs from CYP24A1 gene were predicted to be the causative agents for human diseases. This study will be helpful in selecting potential SNPs for experimental study from the SNP pool and also will reduce the cost for identification of potential SNPs as a genetic marker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mgene.2016.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833053PMC
September 2016

The Binding Mode Prediction and Similar Ligand Potency in the Active Site of Vitamin D Receptor with QM/MM Interaction, MESP, and MD Simulation.

Chem Biol Drug Des 2016 Aug 31;88(2):272-80. Epub 2016 Mar 31.

Pharmacogenomics and CADD Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, 630 004, India.

Non-secosteroidal ligands are well-known vitamin D receptor (VDR) agonists. In this study, we described a combined QM/MM to define the protein-ligand interaction energy a strong positive correlation in both QM-MM interaction energy and binding free energy against the biological activity. The molecular dynamics simulation study was performed, and specific interactions were extensively studied. The molecular docking results and surface analysis shed light on steric and electrostatic complementarities of these non-secosteroidal ligands to VDR. Finally, the drug likeness properties were also calculated and found within the acceptable range. The results show that bulky group substitutions in side chain decrease the VDR activity, whereas a small substitution increased it. Functional analyses of H393A and H301A mutations substantiate their roles in the VDR agonistic and antagonistic activities. Apart from the His393 and His301, two other amino acids in the hinge region viz. Ser233 and Arg270 acted as an electron donor/acceptor specific to the agonist in the distinct ligand potency. The results from this study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cbdd.12754DOI Listing
August 2016

Antidiabetic, antihyperlipidaemic, and antioxidant activity of Syzygium densiflorum fruits in streptozotocin and nicotinamide-induced diabetic rats.

Pharm Biol 2016 Sep 24;54(9):1716-26. Epub 2015 Dec 24.

c Organic Synthesis Group, Department of Chemistry , School of Chemical and Biotechnology, SASTRA University , Thanjavur , Tamil Nadu , India.

Context Syzygium densiflorum Wall. ex Wight & Arn (Myrtaceae) has been traditionally used by local tribes of the Nilgiris, Tamil Nadu, India, for the treatment of diabetes, however, no definitive experimental studies are available. Objective This study investigates the antidiabetic, antihyperlipidaemic and antioxidant activities of ethanol extract of S. densiflorum (EFSD) fruits in streptozotocin (STZ) and nicotinamide (NA)-induced diabetic rats. Materials and methods Acute oral toxicity and oral glucose tolerance were assessed in normal rats. The antidiabetic, antihyperlipidaemic and antioxidant activities were investigated in STZ - NA-induced diabetic rats. Diabetic rats were orally administered with glibenclamide (10 mg/kg b.wt), EFSD (200, 400 and 800 mg/kg b.wt) for 28 d. Further, changes in the blood glucose level (BGL), biochemical parameters, antioxidants were observed and histology of pancreas was performed. Results No toxicity and lethality were observed. Results of the following parameters are represented by treated versus disease control (STZ + NA) groups. BGL (161.33 ± 22.8 versus 476.17 ± 56.58 mg/dl), glycosylated haemoglobin (5.285 ± 0.19 versus 8.05 ± 0.55%), urea (40.32 ± 1.96 versus 75.37 ± 2.91 mg/dl), uric acid (1.2 ± 0.07 versus 2.16 ± 0.05 mg/dl), total cholesterol (89.3 ± 5.14 versus 139.7 ± 5.95 mg/dl) and triglycerides (79.65 ± 2.52 versus 108.9 ± 3.61 mg/dl) were significantly decreased, whereas haemoglobin (11.75 ± 0.73 versus 7.95 ± 0.42 g/dl), high-density lipoprotein cholesterol (14.2 ± 1.11 versus 6.97 ± 0.84 mg/dl), total protein (45%) and liver glycogen (87%) were significantly increased in EFSD-treated diabetic group. Significant changes were observed in the enzymatic and non-enzymatic antioxidants in EFSD-treated groups (p < 0.001). Histopathological examination showed the regeneration of β-cells in Islets of Langerhans. Conclusion This study confirms the antidiabetic, antihyperlipidaemic and antioxidant activities of S. densiflorum fruits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/13880209.2015.1125932DOI Listing
September 2016