Publications by authors named "Lakshmanan Loganathan"

8 Publications

  • Page 1 of 1

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.
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http://dx.doi.org/10.1002/jcb.30069DOI Listing
June 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.
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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.
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http://dx.doi.org/10.1007/s00011-019-01282-4DOI Listing
December 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.
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http://dx.doi.org/10.2174/1389450120666190808101356DOI Listing
February 2021

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.
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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.
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http://dx.doi.org/10.2174/1381612824666181114114513DOI Listing
December 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.
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http://dx.doi.org/10.1080/07391102.2018.1521748DOI Listing
September 2019

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