Browsing by Author "Chakraborty, D."

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2,5-Bis(2,2,2-trifluoroethoxy)phenyl-tethered 1,3,4-Oxadiazoles Derivatives: Synthesis, In Silico Studies, and Biological Assessment as Potential Candidates for Anti-Cancer and Anti-Diabetic Agent
(MDPI, 2022) Shankara, S.D.; Isloor, A.M.; Kudva, A.K.; Raghu, S.V.; Jayaswamy, P.K.; Venugopal, P.P.; Shetty, P.; Chakraborty, D.
In the present work, a series of new 1-{5-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-3-acetyl-2-aryl-2H/methyl derivatives were synthesized through a multistep reaction sequence. The compounds were synthesized by the condensation of various aldehydes and acetophenones with the laboratory-synthesized acid hydrazide, which afforded the Schiff’s bases. Cyclization of the Schiff bases yielded 1,3,4-oxadiazole derivatives. By spectral analysis, the structures of the newly synthesized compounds were elucidated, and further, their anti-cancer and anti-diabetic properties were investigated. To examine the dynamic behavior of the candidates at the binding site of the protein, molecular docking experiments on the synthesized compounds were performed, followed by a molecular dynamic simulation. ADMET (chemical absorption, distribution, metabolism, excretion, and toxicity) prediction revealed that most of the synthesized compounds follow Lipinski’s rule of 5. The results were further correlated with biological studies. Using a cytotoxic assay, the newly synthesized 1,3,4-Oxadiazoles were screened for their in vitro cytotoxic efficacy against the LN229 Glioblastoma cell line. From the cytotoxic assay, the compounds 5b, 5d, and 5m were taken for colony formation assay and tunnel assay have shown significant cell apoptosis by damaging the DNA of cancer cells. The in vivo studies using a genetically modified diabetic model, Drosophila melanogaster, indicated that compounds 5d and 5f have better anti-diabetic activity among the different synthesized compounds. These compounds lowered the glucose levels significantly in the tested model. © 2022 by the authors.
A chemically robust amine-grafted Zn(ii)-based smart supramolecular gel as a regenerative platform for trace discrimination of nitro-antibiotics and assorted environmental toxins
(Royal Society of Chemistry, 2023) Saha, E.; Chhetri, A.; Venugopal, P.P.; Chakraborty, D.; Mitra, J.
Smart supramolecular metallogels are fascinating reusable materials with the potential for a wide range of sustainable applications including the detection of multiple lethal pollutants. We have assembled a chemically robust triazole-containing Zn(ii)-supramolecular gel (ZnGel), where the channels and surface of the gel are strategically decorated with triazole N and appended -NH2 units that are pivotal to ZnGel's efficacy as a multi-sensory probe. ZnGel shows selective fluorescence quenching in the presence of traces of nitro-antibiotics (LOD of nitrofurantoin: 4.62 ppm) and electron-deficient nitrophenols (LOD of 4-nitrophenol: 4.18 ppm), without any prior activation. Density functional theory calculations delineate the importance of the triazole gelator in the turn-off fluorescence response of ZnGel to divergent organo-toxins and substantiate the supramolecular interactions between the ZnGel and the analytes. Significant fluorescence quenching of ZnGel ensued in the presence of a trace amount of Fe3+ (LOD: 6.13 ppm) over other competing metal ions, in addition to visible colorimetric changes in the ZnGel upon metal encapsulation. The quenching ability of ZnGel remains unaltered for multiple cycles toward these environmental pollutants. The noteworthy quenching efficiency is attributed to a combination of static and dynamic fluorescence quenching and resonance energy transfer, which are in harmony with the DFT predictions. Thus, ZnGel provides a platform for the development of gel-based probes for diverse applications in the future. © 2023 The Royal Society of Chemistry.
A new reaction coordinate to study the translocation pathway of cell-penetrating peptides across lipid bilayers: The cases of transportan-10 and penetratin
(American Institute of Physics, 2025) Mathath, A.V.; Chakraborty, D.
Translocation pathway of cell-penetrating peptides remains elusive, as it is hard to observe by experimental and theoretical studies, which limits their effective use. Furthermore, lipid dynamics influence the translocation pathway, which is often overlooked due to its slow timescale. Current studies lack the effect of multiple peptides on the translocation process. Therefore, in this work, we employ the umbrella sampling technique with a preferential lipid–peptide interaction term in the reaction coordinate to explore the translocation activity of penetratin and transportan-10 (TP10) peptides in a heterogeneous membrane. In experiments, they follow different pathways according to their concentration, but the cause of this difference is unknown. We considered single and multiple (two and four) peptide translocation processes to understand the differences. Self-aggregation process is taken into account for multiple peptides. The interaction between peptides and peptides–lipids is found to be important for a proper overview of the translocation process. Peptide translocation was found to be related to the dynamics of the lipids, which change during the translocation process, making the system complex to study. In the case of multiple penetratin translocation, the anionic lipids were found to aggregate on the positive curvature of the upper leaflet, helping fold the membrane. Lipid composition of the TP10 multiple peptide case was found random. The increased mass and size of the solute in this case helped attain a radius more than the threshold value, leading to pore formation. Free energy barriers of single TP10 and penetratin are found to be 45.4 ± 2 and 33.7 ± 0.8 kJ mol?1, respectively. © 2025 Author(s).
Anti-corrosion investigation of a new nitro veratraldehyde substituted imidazopyridine derivative Schiff base on mild steel surface in hydrochloric acid medium: Experimental, computational, surface morphological analysis
(Elsevier Ltd, 2022) Shenoy K, V.; Venugopal, P.P.; Reena Kumari, P.D.; Chakraborty, D.
Intensive research has recently been directed toward synthesizing novel, non-toxic, and cost-effective organic inhibitors against metallic corrosion. In the present investigation, a non-toxic, novel Schiff base inhibitor, 6-bromo-(4,5-dimethoxy-2-nitrophenyl) methylidene] imidazo[1,2-a] pyridine-2-carbohydrazide (NVAIP) was synthesized and tested for its corrosion inhibition performance on Mild Steel (MS) in 1 M HCl at 303–323 K using potentiodynamic polarization study, electrochemical impedance spectroscopy (EIS) measurements, Scanning Electron Microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDX), Atomic Force Microscopy (AFM) and X-Ray Photoelectron Spectroscopy (XPS) analyses. The electrochemical results stated the inhibition effectiveness (ƞ%) of NVAIP was dependent on concentration and temperature, with the maximum efficiency (92.3%) recorded at 303 K for 500 ppm. The mixed-type inhibitory effect of NVAIP was substantiated by the polarization test results. The Langmuir adsorption isotherm model accorded with the metal surface evaluated, and Gibbs free energy of adsorption values ranged from - 35.05 to-36.05 kJ/mol, implying a physical and chemical adsorption mechanism. Surface morphological analysis was carried out to characterize the chemical composition of the adsorbed inhibitor on the MS surface, and these techniques confirmed that the inhibitive layer is composed of an iron oxide/hydroxide mixture where NVAIP molecules are incorporated. Further, the physicochemical and electronic properties of the NVAIP were investigated using Density Functional Theory (DFT) and electrostatic potential energy mapping (ESP). ΔEads value of −57.21 kcal/mol obtained from Molecular Dynamic (MD) simulations correlates well with the experimental results. Moreover, the relevance of the molecular structure of NVAIP and its inhibition act was validated by quantum chemical calculations and molecular dynamic (MD) simulation studies. A possible inhibition mechanism was proposed based on the experimental, theoretical, and surface analysis results. The outcomes of all the techniques show consistent agreement with each other. © 2022 Elsevier B.V.
Carbohelicenes and thiahelicene from phthalaldehydes through Perkin approach
(2019) Sarkar, P.; Das, B.K.; Chakraborty, D.; Muthamma, K.
Synthesis and structural features of helical nanographene molecules comprising of seven benzene rings are examined. Thus dibutyl-dicarboxylate functional [7]helicene and its two regioisomers, dinaphtho[1,2 a:1?,2? h]anthracene and naphtho[2,1 c]pentahelicene, have been synthesized in two steps through Perkin approach using napthalene-2-acetic acid and ortho- or meta-phthalaldehydes. The feasibility of this approach to construct sulfur doped twisted dithiaarenes is also investigated by using thiophene-3-acetic acid. While dithiaarenes from meta-phthalaldehyde remains challenging, synthesis and characterization of planar anthra[1,2 b:5,6 b']dithiophene and twisted 1,12-dithiapentahelicene is successful from ortho-phthalaldehyde. Conformational analysis with DFT calculation shows unique helicity preference in such doubly helical carbon nanostructures. Absorption and emission behavior of these ?-extended molecules shows enhanced conjugation. 2019 Elsevier B.V.
Carbohelicenes and thiahelicene from phthalaldehydes through Perkin approach
(Elsevier B.V., 2019) Sarkar, P.; Das, B.K.; Chakraborty, D.; Muthamma, K.
Synthesis and structural features of helical nanographene molecules comprising of seven benzene rings are examined. Thus dibutyl-dicarboxylate functional [7]helicene and its two regioisomers, dinaphtho[1,2–a:1?,2?–h]anthracene and naphtho[2,1–c]pentahelicene, have been synthesized in two steps through Perkin approach using napthalene-2-acetic acid and ortho- or meta-phthalaldehydes. The feasibility of this approach to construct sulfur doped twisted dithiaarenes is also investigated by using thiophene-3-acetic acid. While dithiaarenes from meta-phthalaldehyde remains challenging, synthesis and characterization of planar anthra[1,2–b:5,6–b']dithiophene and twisted 1,12-dithiapentahelicene is successful from ortho-phthalaldehyde. Conformational analysis with DFT calculation shows unique helicity preference in such doubly helical carbon nanostructures. Absorption and emission behavior of these ?-extended molecules shows enhanced conjugation. © 2019 Elsevier B.V.
Computational insights into factor affecting the potency of diaryl sulfone analogs as Escherichia coli dihydropteroate synthase inhibitors
(2019) Das, B.K.; PV, P.; Chakraborty, D.
Dihydropteroate synthase (DHPS) is an alluring target for designing novel drug candidates to prevent infections caused by pathogenic Escherichia coli strains. Diaryl Sulfone (SO) compounds are found to inhibit DHPS competitively with respect to the substrate pABA (p-aminobenzoate). The extra aromatic ring of diaryl sulfone compounds found to stabilize them in highly flexible pABA binding loops. In this present study, a statistically significant 3D-QSAR model was developed using a data set of diaryl sulfone compounds. The favourable and unfavourable contributions of substitutions in sulfone compounds were illustrated by contour plot obtained from the developed 3D-QSAR model. Molecular docking calculations were performed to investigate the putative binding mode of diaryl sulfone compounds at the catalytic pocket. DFT calculations were carried out using SCF approach, B3LYP- 6-31 G (d) basis set to compute the HOMO, LUMO energies and their respective location at pABA binding pocket. Further, the developed model was validated by FEP (Free Energy Perturbation) calculations. The calculated relative free energy of binding between the highly potent and less potent sulfone compound was found to be ?3.78 kcal/ mol which is comparable to the experimental value of ?5.85 kcal/mol. A 10 ns molecular dynamics simulation of inhibitor and DHPS confirmed its stability at pABA catalytic site. Outcomes of the present work provide deeper insight in designing novel drug candidates for pathogenic Escherichia coli strains. 2018 Elsevier Ltd
Computational insights into factor affecting the potency of diaryl sulfone analogs as Escherichia coli dihydropteroate synthase inhibitors
(Elsevier Ltd, 2019) Das, B.K.; PV, P.; Chakraborty, D.
Dihydropteroate synthase (DHPS) is an alluring target for designing novel drug candidates to prevent infections caused by pathogenic Escherichia coli strains. Diaryl Sulfone (SO) compounds are found to inhibit DHPS competitively with respect to the substrate pABA (p-aminobenzoate). The extra aromatic ring of diaryl sulfone compounds found to stabilize them in highly flexible pABA binding loops. In this present study, a statistically significant 3D-QSAR model was developed using a data set of diaryl sulfone compounds. The favourable and unfavourable contributions of substitutions in sulfone compounds were illustrated by contour plot obtained from the developed 3D-QSAR model. Molecular docking calculations were performed to investigate the putative binding mode of diaryl sulfone compounds at the catalytic pocket. DFT calculations were carried out using SCF approach, B3LYP- 6-31 G (d) basis set to compute the HOMO, LUMO energies and their respective location at pABA binding pocket. Further, the developed model was validated by FEP (Free Energy Perturbation) calculations. The calculated relative free energy of binding between the highly potent and less potent sulfone compound was found to be ?3.78 kcal/ mol which is comparable to the experimental value of ?5.85 kcal/mol. A 10 ns molecular dynamics simulation of inhibitor and DHPS confirmed its stability at pABA catalytic site. Outcomes of the present work provide deeper insight in designing novel drug candidates for pathogenic Escherichia coli strains. © 2018 Elsevier Ltd
Controlling the Morphology and Orientation of the Helical Self-Assembly of Pyrazine Derivatives by Tuning Hydration Shells
(John Wiley and Sons Inc, 2025) Sarkar, S.; Mathath, A.V.; Chakraborty, D.
A combination of density functional theory (DFT) and classical molecular dynamics simulations is performed to unveil the guiding force in the self-assembly process of the pyrazine-based biopolymers to helical nanostructures. The highlight of the study shows the decisive role of the solvent-ligand H-bonding and the inter-molecular pi-pi stacking not only ensures the unidirectional packing of the helical structure but also the rotation of left-handed to the right-handed helical structure of the molecule. This transition is supported by the bulk release of the “ordered” water molecules. The extent of this bonding can be tuned by the temperature, concentration, and type of the metal ions. Smaller ions like Na+ and Al3+ destroy the structure, whereas bigger ions like Zn2+, Ni2+, and Au3+ preserve and rotate the structure according to their concentration. The interaction energy between the pyrazine derivatives is found to be high (?9000 kJ mol?1) for right-handed rotation of the helix, which increases further with the addition of D-histidine, forming a superhelical structure (?10300 kJ mol?1). The insights gained from this work can be used to generate nanostructures of desired morphology. © 2025 Wiley-VCH GmbH.
Deciphering the competitive inhibition of dihydropteroate synthase by 8 marcaptoguanine analogs: enhanced potency in phenylsulfonyl fragments
(Taylor and Francis Ltd., 2022) Das, B.K.; Chakraborty, D.
The emergence of sulfa-drug resistance and reduced efficacy of pterin-based analogs towards Dihydropteroate synthase (DHPS) inhibition dictate a pressing need of developing novel antimicrobial agents for immune-compromised patients. Recently, a series of 8-Marcaptoguanin (8-MG) derivatives synthesized for 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (experimental KD ∼ 100–.0.36) showed remarkable homology with the pteroic-acid and serve as a template for product antagonism in DHPS. The present work integrates ligand-based drug discovery techniques with structure-based docking, enhanced MD simulation, and MM/PBSA techniques to demonstrate the essential features of 8-MG analogs which make it a potent inhibitor for DHPS. The delicate balance in hydrophilic, hydrophobic substitutions on the 8-MG core is the crucial signature for DHPS inhibition. It is found that the dynamic interactions of active compounds are mainly dominated by consistent hydrogen bonding network with Asp 96, Asn 115, Asp 185, Ser 222, Arg 255 and π-π stacking, π-cation interactions with Phe 190, Lys 221. Further, two new 8-MG compounds containing N-phenylacetamide (compound S1, ΔGbind-eff = –62.03 kJ/mol) and phenylsulfonyl (compound S3, ΔGbind-eff = −71.29 kJ/mol) fragments were found to be the most potent inhibitor of DHPS, which stabilize the flexible pABA binding loop, thereby increasing their binding affinity. MM/PBSA calculation shows electrostatic energy contribution to be the principal component in stabilizing the inhibitors in the binding pocket. This fact is further confirmed by the higher energy barrier obtained in umbrella sampling for this class of inhibitors. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
Designing Reaction Coordinate for Ion-Induced Pore-Assisted Mechanism of Halide Ions Permeation through Lipid Bilayer by Umbrella Sampling
(American Chemical Society, 2023) Mathath, A.V.; Das, B.K.; Chakraborty, D.
Ion permeation mechanism through lipid membranes helps to understand cellular processes. We propose new reaction coordinates that allow ions to permeate according to their water affinity and interaction with the hydrophilic layer. Simulations were done for three different halides (F-, Cl-, and I-) in two different lipid bilayers, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dinervonoyl-sn-glycero-3-phosphocholine (DNPC). It is found that the involvement of the water molecules decreases the free energy barrier. The ions were found to follow different pathways for permeation. Formation of proper pores required a collaboration effort of the hydration shell water molecules and the hydrophilic lipid layer, which was favored in the case of Cl- ions. The optimum charge density and good water affinity of Cl- with respect to F- and I- ions helped to form the pore. The effect was prominently seen in the case of DNPC membrane because of its higher hydrophobic thickness. The umbrella sampling results were compared with other methods such as the Markov state model (MSM) and well-tempered metadynamics (WT-metaD). © 2023 American Chemical Society.
Diverse interactions of aggregated insulin with selected coumarin dyes: Time dependent fluorogenicity, simulation studies and comparison with thioflavin T
(Elsevier Ltd, 2021) Dalal, S.; Das, B.K.; Saini, M.; Chakraborty, D.; Sadhu, K.K.
In this study, we have compared neutral coumarin based well-known commercially available probes C6, C7 and C545T for fluorogenic response from the aggregated insulin. The immediate fluorogenic responses were comparatively poor from all the three probes with respect to the previously reported response from thioflavin T (ThT) in the presence of aggregated insulin. Interestingly C6 among the three neutral coumarin derivative showed a significant steady increase of fluorescence intensity with time up to 6 h before reaching the saturation limit. Similar time dependent fluorogenic experiment with C7, C545T and ThT showed comparatively fast saturation within few minutes to 2 h. The molecular docking and simulation studies showed that these neutral probes could be stabilized in the aggregated form of the insulin predominantly by non-covalent weak interactions such as hydrogen bonding, ?-? and cation-? interactions. The probability distributions of the dihedral angles between two heterocyclic parts in C6 showed maximum probability of occurrence at 0° and 180°. These probability distributions of the dihedral angles between two heterocyclic parts within all the four fluorophores provided the justification of selective time dependent fluorescence enhancement from C6 in presence of insulin aggregate. The overall fluorogenic enhancement from C6 was comparable to the fluorogenic response from ThT and theoretical study confirmed distinctly different origin of this associated slow time dependent fluorogenic response. © 2020 Elsevier Ltd
Effect of cosolvents in the preferential binding affinity of water in aqueous solutions of amino acids and amides
(2020) Dilip, H.N.; Chakraborty, D.
Effects of two naturally occurring osmolytes, urea and trimethylamine-N-oxide (TMAO) on the solvation structure of hydrophobic moiety of alanine, glycine, N-methylacetamide and acetamide are investigated by classical molecular dynamics simulations. Our results are analysed in terms of site-site radial distribution functions (RDF), spatial distribution functions (SDF), number of hydrogen bonds, orientation profile, KB integrals, preferential binding coefficient and hydrogen bond dynamics. RDF and SDF showed presence of an extra hydration shell near the hydrophobic unit when TMAO is present in the solution. This hydration shell mainly consists of broken hydrogen bonds. In urea-water solution, intramolecular association is favoured compared to intermolecular association: which is in contrast to the TMAO-water solution. Alanine, glycine, NMA and acetamide showed preferred interactions with the water molecules in presence of TMAO compared to urea. Urea and TMAO both are found to be excluded from the alanine, glycine, NMA and acetamide surface but presence of urea was slightly favoured at higher distances in case of NMA and acetamide. The strong hydrogen bond between TMAO-water increases the hydrogen bond lifetime of other hydrogen bonds in the system. The preferential binding affinity of water with the protein molecules and strong hydrogen bonds are found to be the key reasons for stability in presence of TMAO. 2019 Elsevier B.V.
Effect of cosolvents in the preferential binding affinity of water in aqueous solutions of amino acids and amides
(Elsevier B.V., 2020) Dilip, H.N.; Chakraborty, D.
Effects of two naturally occurring osmolytes, urea and trimethylamine-N-oxide (TMAO) on the solvation structure of hydrophobic moiety of alanine, glycine, N-methylacetamide and acetamide are investigated by classical molecular dynamics simulations. Our results are analysed in terms of site-site radial distribution functions (RDF), spatial distribution functions (SDF), number of hydrogen bonds, orientation profile, KB integrals, preferential binding coefficient and hydrogen bond dynamics. RDF and SDF showed presence of an extra hydration shell near the hydrophobic unit when TMAO is present in the solution. This hydration shell mainly consists of broken hydrogen bonds. In urea-water solution, intramolecular association is favoured compared to intermolecular association: which is in contrast to the TMAO-water solution. Alanine, glycine, NMA and acetamide showed preferred interactions with the water molecules in presence of TMAO compared to urea. Urea and TMAO both are found to be excluded from the alanine, glycine, NMA and acetamide surface but presence of urea was slightly favoured at higher distances in case of NMA and acetamide. The strong hydrogen bond between TMAO-water increases the hydrogen bond lifetime of other hydrogen bonds in the system. The preferential binding affinity of water with the protein molecules and strong hydrogen bonds are found to be the key reasons for stability in presence of TMAO. © 2019 Elsevier B.V.
Effect of hydrophobic and hydrogen bonding interactions on the potency of -alanine analogs of G-protein coupled glucagon receptor inhibitors
(2020) Venugopal, P.P.; Das, B.K.; Soorya, E.; Chakraborty, D.
G-protein coupled glucagon receptors (GCGRs) play an important role in glucose homeostasis and pathophysiology of Type-II Diabetes Mellitus (T2DM). The allosteric pocket located at the trans-membrane domain of GCGR consists of hydrophobic (TM5) and hydrophilic (TM7) units. Hydrophobic interactions with the amino acid residues present at TM5, found to facilitate the favorable orientation of antagonist at GCGR allosteric pocket. A statistically robust and highly predictive 3D-QSAR model was developed using 58 ?-alanine based GCGR antagonists with significant variation in structure and potency profile. The correlation coefficient (R2) and cross-validation coefficient (Q2) of the developed model were found to be 0.9981 and 0.8253, respectively at the PLS factor of 8. The analysis of the favorable and unfavorable contribution of different structural features on the glucagon receptor antagonists was done by 3D-QSAR contour plots. Hydrophobic and hydrogen bonding interactions are found to be main dominating non-bonding interactions in docking studies. Presence of highest occupied molecular orbital (HOMO) in the polar part and lowest unoccupied molecular orbital (LUMO) in the hydrophobic part of antagonists leads to favorable protein-ligand interactions. Molecular mechanics/generalized born surface area (MM/GBSA) calculations showed that van der Waals and nonpolar solvation energy terms are crucial components for thermodynamically stable binding of the inhibitors. The binding free energy of highly potent compound was found to be ?63.475 kcal/mol; whereas the least active compound exhibited binding energy of ?41.097 kcal/mol. Further, five 100 ns molecular dynamics simulation (MD) simulations were done to confirm the stability of the inhibitor-receptor complex. Outcomes of the present study can serve as the basis for designing improved GCGR antagonists. 2019 Wiley Periodicals, Inc.
Effect of hydrophobic and hydrogen bonding interactions on the potency of ß-alanine analogs of G-protein coupled glucagon receptor inhibitors
(John Wiley and Sons Inc. P.O.Box 18667 Newark NJ 07191-8667, 2020) Venugopal, P.P.; Das, B.K.; Soorya, E.; Chakraborty, D.
G-protein coupled glucagon receptors (GCGRs) play an important role in glucose homeostasis and pathophysiology of Type-II Diabetes Mellitus (T2DM). The allosteric pocket located at the trans-membrane domain of GCGR consists of hydrophobic (TM5) and hydrophilic (TM7) units. Hydrophobic interactions with the amino acid residues present at TM5, found to facilitate the favorable orientation of antagonist at GCGR allosteric pocket. A statistically robust and highly predictive 3D-QSAR model was developed using 58 ?-alanine based GCGR antagonists with significant variation in structure and potency profile. The correlation coefficient (R2) and cross-validation coefficient (Q2) of the developed model were found to be 0.9981 and 0.8253, respectively at the PLS factor of 8. The analysis of the favorable and unfavorable contribution of different structural features on the glucagon receptor antagonists was done by 3D-QSAR contour plots. Hydrophobic and hydrogen bonding interactions are found to be main dominating non-bonding interactions in docking studies. Presence of highest occupied molecular orbital (HOMO) in the polar part and lowest unoccupied molecular orbital (LUMO) in the hydrophobic part of antagonists leads to favorable protein-ligand interactions. Molecular mechanics/generalized born surface area (MM/GBSA) calculations showed that van der Waals and nonpolar solvation energy terms are crucial components for thermodynamically stable binding of the inhibitors. The binding free energy of highly potent compound was found to be ?63.475 kcal/mol; whereas the least active compound exhibited binding energy of ?41.097 kcal/mol. Further, five 100 ns molecular dynamics simulation (MD) simulations were done to confirm the stability of the inhibitor-receptor complex. Outcomes of the present study can serve as the basis for designing improved GCGR antagonists. © 2019 Wiley Periodicals, Inc.
Effect of peptide hydrophilicity on membrane curvature and permeation
(American Institute of Physics, 2024) Mathath, A.V.; Chakraborty, D.
Using a well-developed reaction coordinate in umbrella sampling, we studied the single peptide permeation through a model cancerous cell membrane, varying the hydrophilicity and the charge of the peptides. Two peptides, melittin and pHD108, were studied. The permeation mechanism differs from a barrel-stave-like mechanism to toroidal pore and vesicle formation based on the number and the placement of the hydrophilic amino acids in the peptide. Membrane curvature changes dynamically as the permeation process occurs. In the case of vesicles, the peptide traverses along a smooth, homogenous pathway, whereas a rugged, steep pathway was found when lipid molecules did not line up along the wall of the membrane (barrel-stave-like mechanism). A mechanism similar to a toroidal pore consists of multiple minima. Higher free energy was found for the permeating terminal containing charged amino acid residues. Vesicle formation was found for pHD108 peptide N-terminal with a maximum membrane thinning effect of 54.4% with free energy cost of 8.20 ± 0.10 kcal mol?1 and pore radius of 2.33 ± 0.07 nm. Insights gained from this study can help to build synthetic peptides for drug delivery. © 2024 Author(s).
Effect of Water Models on The Stability of RNA: Role of Counter-Ions
(Elsevier B.V., 2023) Singh, O.; Venugopal, P.P.; Chakraborty, D.
Various force fields and water model potentials influence significantly RNA conformations. The polyanionic nature of RNA attracts the water molecules and the counter ions which in turn affects their stability. The interfacial water's structural and dynamic aspects affect the RNA's base-pair opening and denaturation by breaking or making inter/intra-hydrogen bonds. Herein, we employed an MD simulations study using SPC/E and modified TIP3P water models in combination with different force fields CHARMM and AMBER to find their influence on the hydration shell of the SARS-CoV-2 RNA genome at different temperatures. AMBER-mTIP3P model was found to give more dynamic and transient conformations for RNA. The lower dielectric constant of the SPC/E model helps in the formation of the ion-contact pair near the negatively charged phosphate group (Na+-PO4−) leading to strong RNA-ion interaction and strong hydration shells having higher hydrogen bond lifetime. The Na+ ion survival probability at the interface was found to be more in the SPC/E model. At lower temperatures, the water molecules inside these hydration shells were found to be inhomogeneous, with lower void space, higher-coordinated, and non-tetrahedral. The higher dielectric constant of the mTIP3P model screened out the attraction between the ion pairs leading to a more homogenous solvation shell having a lesser hydrogen bond lifetime and more diffusive water. The distribution of the ions near the RNA structure is confirmed by metadynamics simulations. Both water models were found to disrupt the base pair orientation due to the formation of water bridges between the O2ʹ group of RNA and the water molecules. © 2023 The Author(s)
Effective inhibition of mild steel corrosion by 6-bromo-(2,4-dimethoxyphenyl)methylidene]imidazo [1,2-a]pyridine-2-carbohydrazide in 0.5 M HCl: Insights from experimental and computational study
(Elsevier B.V., 2021) Vranda Shenoy, K.; Venugopal, P.P.; Reena Kumari, P.D.; Chakraborty, D.
A new inhibitor, 6-bromo-(2,4-dimethoxyphenyl)methylidene]imidazo [1,2-a]pyridine-2-carbohydrazide (DMPIP) was evaluated as a corrosion inhibitor for Mild Steel (MS) in 0.5 M HCl solution at 303–323 K using potentiodynamic polarization and electrochemical impedance spectroscopic (EIS) techniques. Both the techniques confirmed an increase in inhibition efficiency with the concentration of DMPIP but decrease with temperature. The highest inhibitive action (96.7%) was registered at 303 K for 500 ppm of DMPIP concentration. Polarization study revealed mixed inhibition action by DMPIP. Nyquist plot obtained for MS using EIS technique showed two capacitive loops on addition of inhibitor to HCl solution confirmed the inhibitory action of DMPIP via adsorption at the metal/solution interface. The surface morphology analysis was carried out by SEM, EDX and FTIR techniques. The adsorption process was demonstrated using Langmuir's adsorption isotherm model. The thermodynamic parameters (?Goads, ?Hoads) indicated that the adsorption was spontaneous and done by physisorption. Further, quantum chemical studies using Density Functional Theory (DFT) elucidated that the formation of Fe-DMPIP complex presumably due to the interaction of protonated form of DMPIP with the empty d orbitals of the iron atom. © 2021 Elsevier B.V.
Epitope-Based Potential Vaccine Candidate for Humoral and Cell-Mediated Immunity to Combat Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic
(American Chemical Society, 2020) Das, B.K.; Chakraborty, D.
The emergence of severe acute respiratory syndrome from novel Coronavirus (SARS-CoV-2) has put an immense pressure worldwide where vaccination is believed to be an efficient way for developing hard immunity. Herein, we employ immunoinformatic tools to identify B-cell, T-cell epitopes associated with the spike protein of SARS-CoV-2, which is important for genome release. The results showed that the highly immunogenic epitopes located at the stalk part are mostly conserved compared to the receptor binding domain (RDB). Further, two vaccine candidates were computationally modeled from the linear B-cell, T-cell epitopes. Molecular docking reveals the crucial interactions of the vaccines with immune-receptors, and their stability is assessed by MD simulation studies. The chimeric vaccines showed remarkable binding affinity toward the immune cell receptors computed by the MM/PBSA method. van der Waals and electrostatic interactions are found to be the dominant factors for the stability of the complexes. The molecular-level interaction obtained from this study may provide deeper insight into the process of vaccine development against the pandemic of COVID-19. © 2020 American Chemical Society.