Online ISSN: 2515-8260

Keywords : ADME

SARS-CoV2 multiple target inhibitors from Andrographis Paniculata: An in-silico report

Karthikeyan Swaminathan; Kavinkumar Nirmala Karunakaran; Jeevitha priya Manoharan; Subramanian Vidyalakshmi

European Journal of Molecular & Clinical Medicine, 2021, Volume 8, Issue 3, Pages 1653-1685

Coronavirus Disease – 2019 (COVID–19) caused by the novel coronavirus, SARS-CoV2 has plagued the world in pandemic for the past few months. Currently, many groups are investigating on a potent candidate for treating this highly infectious disease. Phytocompounds from many medicinal plants are reported to possess anti-viral and anti-inflammatory properties. The current study emphasizes on evaluating the inhibition efficacy of the phytocompounds from Andrographis paniculata against 10 structural and non-structural SARS-CoV2 proteins by virtual screening. Molecular docking, binding interactions, ADME and toxicity profiling of the selected fifty one phytocompounds were analysed and compared against 10 well studied repurposed drugs. The best docked complexes were subjected to MD simulation for 50 nanoseconds and the compound stigmasterol was observed to be outperforming in the simulation studies. We report that A.paniculata constitutes 65.78% druggable phytocompounds against SARS‐CoV2. We found that the two phytosterols, stigmasterol and stigmasta-5,22-dien-3-ol act as potential lead molecules against multiple target proteins of SARS–CoV2. Based on the literature evidence on Andrographis paniculata and our detailed analysis, this plant and its phytocompounds could be repurposed as a potential anti-COVID agent.

Binding Affinity Of Omega 3 Fatty Acid As An Agonist PPAR- And GPR120 Receptor For Obesity Using Molecular Docking And ADME Prediction

Ginna Megawati; Dewi M.D Herawati; Ida Musfiroh

European Journal of Molecular & Clinical Medicine, 2020, Volume 7, Issue 10, Pages 1686-1695

Obesity is a complex disease involving excessive amounts of body fat due to problems with lipid metabolism and catalysis by PPARγ and GPR120. It is currently known that full-agonist drugs PPRγ have cardiovascular side effects and are closely related to lipid metabolism by GPR120. The selected of omega-3 derivative compounds is based on an important role in morphological, biochemical, molecular brain development and has been shown to control body weight by reducing body fat accumulation. The aim of this study was to obtain information regarding the binding affinity of 9 selected compounds from omega-3 to PPARγ and GPR120 either as full agonist or partial agonist by showing that these compounds using absorption and distribution prediction (ADME) sufficiently reasonable. Docking analysis was performed using Auto Dock 4.2, and ADME prediction using PreADMET software. The results showed that DPA and DHA have most higher binding affinity of molecular docking at the active site of the partial agonis and full agonist for PPARγ with free energy -9.26 kcal/mol and -8.92, respectively. DPA showed capabilities as partial agonist is characterized by a hydrogen bond in the form of Ser342 such as telmisartan, while DHA has a similar hydrogen bond in the form of Ile281 such as rosiglitazone. Whereas the results for GPR120 showed that DHA, EPA, and ETA compounds had good potential activity as agonists by binding to the same amino acid residues Arg327 and Tyr146, and the compounds have the lowest bond energies were -9.4, -8.72 and -8.15 kcal/ mol, respectively compared to the neurotensin ligand is -6.31 kcal/mol. All compounds meet absorption and distribution parameters, so that the selected compounds have the potential to prevent obesity through PPARγ and GPR120

Discovery of Aminoglycoside Derivatives as a Potent Inhibitor for the Prognostic P4HA1 gene in Breast Cancer: A Holistic Genomic and Virtual Screening Approach.

Manikandan Murugesan; Premkumar Kumpati

European Journal of Molecular & Clinical Medicine, 2020, Volume 7, Issue 6, Pages 920-941

Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1) is a catalytic enzyme that involves synthesis of collagen and extracellular matrix interactions. Aberrant expression of P4HA1 promotes carcinogenetic invasion and metastasis in breast cancer. In this study, we combined transcriptomic and drug repositioning approach for the intervention of new targeted anti-cancer therapy for breast cancer. The mRNA expression, copy number variation, mutation and clinical patient’s outcome of P4HA1 validated through cBioportal. High-throughput virtual screening and MM-GBSA analysis were performed with Drugbank approved molecules (9,612) for identifying the potent therapeutic drug molecules against P4HA1 using Schrodinger. The cBioportal based gene expression of P4HA1 in the TCGA-breast cancer cohort revealed significant elevated expression in the breast tumor compared to the normal. Subsequently, the high copy number amplification and mRNA expression was high in the invasive breast carcinoma compared to the other subtypes. In addition, the overall survival was validated with median P4HA1 expression and conferred with poor prognosis of breast cancer patients. Further, receptor based virtual screening identified top hits of aminoglycoside derivatives, amikacin (glide score −9.58 kcal/mol) and gentamicin (glide score −7.02 kcal/mol) with best docking score and stable interaction with favorable amino acid residues of P4HA1 includes Glu171, Asp178, Lys213, Lys 206 and Leu174. Moreover, both the drug passed the drug-likeness property (ADME) and MM-GBSA energy model. This study integrates genomic and molecular docking approach, suggests P4HA1 as a prognostic biomarker and selective inhibition might be therapeutically involved in the breast cancer intervention.