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1.
Comput Biol Chem ; 107: 107964, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37820470

ABSTRACT

Diabetes mellitus Type 2 (DM2T) is a rapidly expanding metabolic endocrine disorder worldwide. It is caused due to inadequate insulin secretion by pancreatic beta cells as well as development of insulin resistance. This study aimed to investigate the anti-α-glucosidase, insulin stabilization effect, and non-cytotoxic nature of Gymnema latifolium leaf aqueous extract (GLAE). FTIR analysis revealed the functional groups of compounds present in GLAE. Through LC/ESI-MS/MS analysis, about 12 compounds which belongs to different classes, triterpene glycosides, flavonoids, phenolics, stilbene glycosides and chlorophenolic glycosides were identified. GLAE showed in vitro antioxidant activity. GLAE stabilized insulin by increasing its α-helical content. GLAE inhibited the mammalian α-glucosidase (IC50 = 144 µg/mL) activity through competitive mode (Ki = 61.30 µg/mL). GLAE did not affect the viability of normal cell line (Vero cell line) which shows its non-toxic nature. Molecular docking of phytocompounds identified in GLAE was done with human α-glucosidase and insulin. The top 2 compounds [Gymnema saponin V (GSV) and quercetin 3-(2-galloylglucoside) (QGG) with α-glucosidase; GSV and Z)-resveratrol 3,4'-diglucoside (RDG) with human insulin] with low binding free energy were subjected to 100 ns molecular dynamics simulation to ascertain the stable binding of ligand with protein. The MM/GBSA analysis revealed binding free energy of GSV/α-glucosidase and QGG /α-glucosidase to be - 20.9935 and, - 30.9461 kcal/mol, respectively. Altogether GLAE is valuable source of anti-α-glucosidase inhibitors and insulin stabilizing compounds, suggesting potential lead for further exploration as complementary medicine against DM2T.


Subject(s)
Gymnema , Insulins , Animals , Humans , alpha-Glucosidases/metabolism , Glycosides/analysis , Insulins/analysis , Molecular Docking Simulation , Phytochemicals/pharmacology , Plant Extracts/chemistry , Plant Leaves/chemistry , Tandem Mass Spectrometry
2.
J Cell Biochem ; 124(8): 1115-1134, 2023 08.
Article in English | MEDLINE | ID: mdl-37435893

ABSTRACT

Currently, no approved drug is available as a causative agent of coronavirus disease 2019 (COVID-19) except for some repurposed drugs. The first structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in late 2019, based on that some vaccines and repurposed drugs were approved to prevent people from COVID-19 during the pandemic situation. Since then, new types of variants emerged and notably, the receptor binding domain (RBD) adopted different binding modes with angiotensin-converting enzyme 2 (ACE2); this made significant changes in the progression of COVID-19. Some of the new variants are highly infectious spreading fast and dangerous. The present study is focused on understanding the binding mode of the RBD of different mutated SARS-CoV-2 variants of concern (alpha to omicron) with the human ACE2 using molecular dynamics simulation. Notably, some variants adopted a new binding mode of RBD with ACE2 and formed different interactions, which is unlike the wild type; this was confirmed from the comparison of interaction between RBD-ACE2 of all variants with its wild-type structure. Binding energy values confirm that some mutated variants exhibit high binding affinity. These findings demonstrate that the variations in the sequence of SARS-CoV-2 S-protein altered the binding mode of RBD; this may be the reason that the virus has high transmissibility and causes new infections. This in-silico study on mutated variants of SARS-CoV-2 RBD with ACE2 insights into their binding mode, binding affinity, and stability. This information may help to understand the RBD-ACE2 binding domains, which allows for designing newer drugs and vaccines.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Angiotensin-Converting Enzyme 2/genetics , Molecular Dynamics Simulation , Mutation , Protein Binding , SARS-CoV-2/genetics
3.
J Biomol Struct Dyn ; : 1-14, 2023 Jun 10.
Article in English | MEDLINE | ID: mdl-37301607

ABSTRACT

Since 2019 the SARS-CoV-2 and its variants caused COVID-19, such incidents brought the world in pandemic situation. This happened due to furious mutations in SARS-CoV-2, in which some variants had high transmissibility and infective, this led the virus emerged as virulent and worsened the COVID-19 situation. Among the variants, P323L is one of the important mutants of RdRp in SARS-CoV-2. To inhibit the erroneous function of this mutated RdRp, we have screened 943 molecules against the P323L mutated RdRp with the criteria that the molecules with 90% similar to the structure of remdesivir (control drug) resulted nine molecules. Further, these molecules were evaluated by induced fit docking (IFD) identified two molecules (M2 & M4) which are forming strong intermolecular interactions with the key residues of mutated RdRp and has high binding affinity. Docking score of the M2 and M4 molecules with mutated RdRp are -9.24 and -11.87 kcal/mol, respectively. Further, to understand the intermolecular interactions, conformational stability, the molecular dynamics simulation and binding free energy calculations were performed. The binding free energy values of M2 and M4 molecules with the P323L mutated RdRp complexes are -81.60 and -83.07 kcal/mol, respectively. The results of this in silico study confirm that M4 is a potential molecule; hence, it may be considered as the potential inhibitor of P323L mutated RdRp to treat COVID-19 after clinical investigation.Communicated by Ramaswamy H. Sarma.

4.
J Biomol Struct Dyn ; 41(23): 13752-13765, 2023.
Article in English | MEDLINE | ID: mdl-36905654

ABSTRACT

Lawsonia inermis (henna) has been used in traditional medicine throughout the world and biological property of its flower has been least explored. In the present study, the phytochemical characterization and biological activity (in vitro radical scavenging activity, anti-alpha glucosidase and anti-acetylcholinesterase) of aqueous extract prepared from henna flower (HFAE) was carried out by both Qualitative and quantitative phytochemical analysis and Fourier-transform infrared spectroscopy revealed the functional group of the phytoconstituents such as phenolics, flavonoids, saponin, tannins and glycosides. The phytochemicals present in HFAE was preliminary identified by liquid chromatography/electrospray ionization tandem mass spectrometry. The HFAE showed potent in vitro antioxidant activity and the HFAE inhibited mammalian α-glucosidase (IC50 = 129.1 ± 5.3 µg/ml; Ki = 38.92 µg/ml) and acetylcholinesterase (AChE; IC50 = 137.77 ± 3.5 µg/ml; Ki = 35.71 µg/ml) activity by competitive manner. In silico molecular docking analysis revealed the interaction of active constituents identified in HFAE with human α-glucosidase and AChE. Molecular dynamics simulation for 100 ns showed the stable binding of top two ligand/enzyme complexes with lowest binding energy such as 1,2,3,6-Tetrakis-O-galloyl-beta-D-glucose (TGBG)/human α-glucosidase, Kaempferol 3-glucoside-7-rhamnoside (KGR)/α-glucosidase, agrimonolide 6-O-ß-D-glucopyranoside (AMLG)/human AChE and KGR/AChE. Through MM/GBSA analysis, the binding energy for TGBG/human α-glucosidase, KGR/α-glucosidase, AMLG/human AChE and KGR/AChE was found to be -46.3216, -28.5772, -45.0077 and -47.0956 kcal/mol, respectively. Altogether, HFAE showed an excellent antioxidant, anti-alpha glucosidase and anti-AChE activity under in vitro. This study suggest HFAE with remarkable biological activities could be further explored for therapeutics against type 2 diabetes and diabetes-associated cognitive decline.Communicated by Ramaswamy H. Sarma.


Subject(s)
Diabetes Mellitus, Type 2 , Lawsonia Plant , Animals , Humans , alpha-Glucosidases/metabolism , Plant Extracts/pharmacology , Plant Extracts/chemistry , Molecular Dynamics Simulation , Lawsonia Plant/metabolism , Molecular Docking Simulation , Acetylcholinesterase/metabolism , Flowers/chemistry , Flowers/metabolism , Phytochemicals/pharmacology , Phytochemicals/chemistry , Antioxidants/pharmacology , Antioxidants/chemistry , Mammals/metabolism
5.
J Biomol Struct Dyn ; 41(4): 1351-1365, 2023 03.
Article in English | MEDLINE | ID: mdl-34974819

ABSTRACT

The p300 histone acetyltransferase (HAT) enzyme acetylates the lysine residue of histone promotes the transcription reaction. The abnormal function of p300 HAT enzyme causes various diseases such as Cancer, Asthma, Alzheimer, Diabetics, and AIDS. In the recent years, several studies have been conducted to design potential drug to inhibit this enzyme. Recently, an in vitro study has been performed on the synthetic molecules PU139 and PU141 to inhibit the p300 HAT enzyme. The present study aims to understand the binding affinity, intermolecular interactions, conformational stability and binding energy of PU139 and PU141 molecules in the active site of p300 HAT enzyme from the in silico studies. The molecular docking and molecular dynamics (MD) simulations were carried out for both ligands with the p300 HAT enzyme. The molecular docking and MD simulations reveals that both molecules forms expected interactions with the catalytic site key residues of p300 enzyme. The MD simulation shows the maximum RMSD value for the PU141 is 2.3 Å, whereas for PU139 is 3.3 Å; these low RMSD values indicate that both molecules are highly stable in the active site of p300. The calculated binding free energy of PU141 (-20.62 kcal/mol) is higher than the molecule PU139 (-17.67 kcal/mol). Among the results, PU141 shows the high binding affinity with p300 while comparing with PU139. The results of this in-silico study coupled with the findings reported in the in vitro study confirm that PU141 may be suitable for clinical study.Communicated by Ramaswamy H. Sarma.


Subject(s)
Histone Acetyltransferases , Molecular Dynamics Simulation , Molecular Docking Simulation , Histone Acetyltransferases/chemistry , Catalytic Domain , Histones/metabolism
6.
J Biomol Struct Dyn ; 41(20): 10396-10410, 2023 12.
Article in English | MEDLINE | ID: mdl-36510678

ABSTRACT

In this COVID-19 pandemic situation, an appropriate drug is urgent to fight against this infectious disease to save lives and prevent mortality. Repurposed drugs and vaccines are the immediate solutions for this medical emergency until discover a new drug to treat this disease. As of now, no specific drug is available to cure this disease completely. Several drug targets were identified in SARS-CoV-2, in which RdRp protein is one of the potential targets to inhibit this virus infection. In-Silico studies plays a vital role to understand the binding nature of the drugs at the atomic level against the disease targets. The present study explores the binding mechanism of reported 53 nucleoside and non-nucleoside RdRp inhibitors and Ivermectin which are in clinical trials. These molecules were screened by molecular docking simulation; in which, the molecules are showing high binding affinity and forming interactions with the key amino acids of active site of RdRp protein are chosen for molecular dynamics simulation (MD) and binding free energy analysis. The results of molecular docking and MD simulation studies reveal that IDX184 is a stable molecule and forms strong interactions with the key amino acids and shows high binding affinity towards RdRp. Hence, IDX184 may also be considered as a potential inhibitor of RdRp after clinical study.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Molecular Dynamics Simulation , Nucleosides/pharmacology , Molecular Docking Simulation , Pandemics , Amino Acids , RNA-Dependent RNA Polymerase , Antiviral Agents/pharmacology
7.
Molecules ; 27(12)2022 Jun 20.
Article in English | MEDLINE | ID: mdl-35745085

ABSTRACT

The high expression of 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1) mRNA has been found in breast cancer tissues and endometriosis. The current research focuses on preparing a range of organic molecules as 17ß-HSD1 inhibitors. Among them, the derivatives of hydroxyphenyl naphthol steroidomimetics are reported as one of the potential groups of inhibitors for treating estrogen-dependent disorders. Looking at the recent trends in drug design, many halogen-based drugs have been approved by the FDA in the last few years. Here, we propose sixteen potential hydroxyphenyl naphthol steroidomimetics-based inhibitors through halogen substitution. Our Frontier Molecular Orbitals (FMO) analysis reveals that the halogen atom significantly lowers the Lowest Unoccupied Molecular Orbital (LUMO) level, and iodine shows an excellent capability to reduce the LUMO in particular. Tri-halogen substitution shows more chemical reactivity via a reduced HOMO-LUMO gap. Furthermore, the computed DFT descriptors highlight the structure-property relationship towards their binding ability to the 17ß-HSD1 protein. We analyze the nature of different noncovalent interactions between these molecules and the 17ß-HSD1 using molecular docking analysis. The halogen-derived molecules showed binding energy ranging from -10.26 to -11.94 kcal/mol. Furthermore, the molecular dynamics (MD) simulations show that the newly proposed compounds provide good stability with 17ß-HSD1. The information obtained from this investigation will advance our knowledge of the 17ß-HSD1 inhibitors and offer clues to developing new 17ß-HSD1 inhibitors for future applications.


Subject(s)
Halogens , Molecular Dynamics Simulation , 17-Hydroxysteroid Dehydrogenases , Enzyme Inhibitors/pharmacology , Female , Humans , Molecular Docking Simulation , Naphthols , Structure-Activity Relationship
8.
Acta Crystallogr C Struct Chem ; 78(Pt 3): 181-191, 2022 03 01.
Article in English | MEDLINE | ID: mdl-35245215

ABSTRACT

The proton-transfer complexes 2-amino-4-methoxy-6-methylpyrimidinium (2A4M6MP) 4-aminosalicylate (4AMSA), C6H10N3O+·C7H6NO3-, I, and 5-chlorosalicylate (5ClSA), C6H10N3O+·C7H4ClO3-, II, were synthesized by slow evaporation and crystallized. The crystal structures of both I and II were determined by single-crystal X-ray structure analysis. The crystal structures of both salts exhibit O-H...O, N-H...O, N-H...N and C-H...O interactions in their crystals. The 4AMSA and 5ClSA anions in combination with the 2A4M6MP cations form distinct synthons, which are represented by the graph-set notations R22(8), R42(8) and R22(8). Furthermore, the ΔpKa values were calculated and clearly demonstrate that 2A4M6MP is a good salt former when combined with carboxylic acids. Hirshfeld surface analysis was used to quantify the weak and strong interactions in the solid state, and energy framework calculations showed the stability of the hydrogen-bonding interactions. QTAIM (quantum theory of atoms in molecules) analysis revealed the nature of the chemical bonding in I and II, and the charge-density distribution in the intermolecular interactions in the crystal structures.


Subject(s)
Quantum Theory , Salts , Crystallography, X-Ray , Hydrogen Bonding , Salicylates
9.
Appl Biochem Biotechnol ; 193(6): 1909-1923, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33512650

ABSTRACT

The unprecedented coronavirus SARS-CoV-2 outbreak at Wuhan, China, caused acute respiratory infection to humans. There is no precise vaccine/therapeutic agents available to combat the COVID-19 disease. Some repurposed drugs are saving the life of diseased, but the complete cure is relatively less. Several drug targets have been reported to inhibit the SARS-CoV-2 virus infection, in that TMPRSS2 (transmembrane protease serine 2) is one of the potential targets; inhibiting this protease stops the virus entry into the host human cell. Camostat mesylate, nafamostat, and leupeptin are the drugs, in which the first two drugs are being used for COVID-19 and leupeptin also tested. To consider these drugs as the repurposed drug for COVID-19, it is essential to understand their binding affinity and stability with TMPRSS2. In the present study, we performed the molecular docking and molecular dynamics (MD) simulation of these molecules with the TMPRSS2. The docking study reveals that leupeptin molecule strongly binds with TMPRSS2 protein than the other two drug molecules. The RMSD and RMSF values of MD simulation confirm that leupeptin and the amino acids of TMPRSS2 are very stable than the other two molecules. Furthermore, leupeptin forms interactions with the key amino acids of TMPRSS2 and the same have been maintained during the MD simulations. This structural and dynamical information is useful to evaluate these drugs to be used as repurposed drugs, however, the strong binding profile of leupeptin with TMPRSS2, suggests, it may be considered as a repurposed drug for COVID-19 disease after clinical trial.


Subject(s)
Antiviral Agents/pharmacology , Benzamidines/therapeutic use , COVID-19 Drug Treatment , Drug Repositioning , Esters/therapeutic use , Guanidines/therapeutic use , Leupeptins/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Serine Endopeptidases/metabolism , Antiviral Agents/therapeutic use , Benzamidines/pharmacology , COVID-19/virology , Esters/pharmacology , Guanidines/pharmacology , Humans , Protein Binding , SARS-CoV-2/drug effects
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