Computational evaluation on molecular stability, reactivity, and drug potential of frovatriptan from DFT and molecular docking approach

Basha S.J., Chamundeeswari S.P., Muthu S., Raajaraman B.

Quantum chemical density functional theory approach (DFT) and vibrational spectroscopy investigation were done on one of the benzimidazole derivatives called 6-Aminobenzimidazole (6ABM). The B3LYP method and 6–311++G (d,p) basis set were used to get the optimized structure, vibrational frequencies, and other various parameters. Atoms in molecules theory were employed to find the binding energies, ellipticity and isosurface projection by electron localization function. The various functional groups are identified using FT-IR, FT-Raman and NMR spectra and compared with the scaled value of simulated spectra. The donor and acceptor interactions are studied by NBO analysis. The reactive areas of the molecule are obtained by molecular electrostatic potential (MEP) and Fukui functions. By using the UV–Vis spectrum the maximum absorption wavelength was obtained and compared with TD-DFT/PCM method with different solvents. The biological studies like drug-likeness and molecular docking are carried out on the molecule.

Daina A., Michielin O., Zoete V.

Abstract SwissTargetPrediction is a web tool, on-line since 2014, that aims to predict the most probable protein targets of small molecules. Predictions are based on the similarity principle, through reverse screening. Here, we describe the 2019 version, which represents a major update in terms of underlying data, backend and web interface. The bioactivity data were updated, the model retrained and similarity thresholds redefined. In the new version, the predictions are performed by searching for similar molecules, in 2D and 3D, within a larger collection of 376 342 compounds known to be experimentally active on an extended set of 3068 macromolecular targets. An efficient backend implementation allows to speed up the process that returns results for a druglike molecule on human proteins in 15–20 s. The refreshed web interface enhances user experience with new features for easy input and improved analysis. Interoperability capacity enables straightforward submission of any input or output molecule to other on-line computer-aided drug design tools, developed by the SIB Swiss Institute of Bioinformatics. High levels of predictive performance were maintained despite more extended biological and chemical spaces to be explored, e.g. achieving at least one correct human target in the top 15 predictions for >70% of external compounds. The new SwissTargetPrediction is available free of charge (www.swisstargetprediction.ch).

UPENDRA C GALGATTE, PRAVIN D CHAUDHARI

Objective: The main objective of the present research work was to develop, optimize, and characterize microemulsion (ME) of frovatriptan succinate to improve brain transport. Methods: The pseudoternary phase diagrams were constructed for ME formulations composed of Capmul MCM, Cremophor EL, and propylene glycol. Frovatriptan succinate-loaded ME was optimized by simplex lattice design having the concentration of oil, surfactant, and cosurfactant representing three apex points on the triangle. These were taken as independent variables and percentage drug release as a response variable. All developed batches of ME were characterized for in vitro tests, histopathology study, and pharmacokinetics in Swiss albino rats. Results: Clear MEs were obtained. F5 having particle size – 142.0 nm, zeta potential – 17.7–−7.8 mv, refractive index – 1.38±0.20, drug content – 98.24±0.20%, and drug diffused through dialysis membrane – 85% was the optimized batch. Drug permeation through the nasal mucosa of F5 in the ex vivo study was found to be 82.32%. Histopathology microscopic study has shown that F5 does not cause any irritation and structural changes in sheep nasal mucosa. The pharmacokinetic parameters were determined after nasal and oral administration of F5. For brain tissue, after nasal administration were Cmax181±1.51 ng/ml, Tmax – 2±1.01, area under curve (AUC)0−6 – 390.0±2.08 ng.h/ml. The AUC0−6 attained by nasal ME was 3.29 times greater than oral solution. Drug targeting index of frovatriptan succinate was 2.06. This was found satisfactory. Conclusion: Microemulsion of said composition was found to be enhancing delivery of frovatriptan succinate to brain tissues through nasal route.

Singh R., Kaur P., Sachdeva R., Grewal J.S., Sathe V., Saini G.S.

Optimized structure of coumarin 500 has been obtained in gas phase and in solvents like methanol, ethanol, dimethyl sulfoxide and CCl4 using density functional theory calculations with B3LYP/6–311 + G(d, p) functionals. The calculated frequencies of certain vibrational bands of coumarin 500 are observed to shift in solvents. To understand the origin of these shifts, HOMO-LUMO analysis of ultra-violet visible spectra of coumarin 500 has been carried out in different solvents. The detailed study of charge transfer interactions in coumarin 500 is done using natural bonding orbital and molecular electrostatic potential analysis. Assignments of various vibrational bands have been obtained and effect of charge transfer interactions in solvents on these bands has been studied.

Joshi B.D., Srivastava A., Tandon P., Jain S., Ayala A.P.

Plant based natural products cover a major sector of the medicinal field, as such focus on plant research has been increased all over the world. As an attempt to aid that research, we have performed structural and spectroscopic analysis of a natural product, an alkaloid: canadine. Both ab initio Hartree-Fock (HF) and density functional theory (DFT) employing B3LYP using 6-311++G(d,p) basis set were used for the calculations. The calculated vibrational frequencies were scaled and compared with the experimental infrared and Raman spectra. The complete vibrational assignments were made using potential energy distribution. The structure-activity relation has also been interpreted by mapping electrostatic potential surface and evaluating the reactivity descriptors, which are valuable information for quality control of medicines and drug-receptor interactions. Natural bond orbital analysis has also been performed to understand the stability and hyperconjugative interactions of the molecule. Furthermore, UV-Vis spectra have been recorded in an ethanol solvent (EtOH) and the electronic property has been analyzed employing TD-DFT for both gaseous and solvent phase. The HOMO and LUMO calculation with their energy gap show that charge transfer occurs within the molecule. Additionally, the nonlinear optical properties of the title compound have been interpreted that predicts it's the best candidate for the NLO materials.

Mennini N., Orlandini S., Furlanetto S., Pasquini B., Mura P.

Frovatriptan is a potent anti-migraine agent with unfavourable slow onset of action, available on the market as film-coated tablets.Optimization, by Quality by Designs strategies, of an orally disintegrating tablet (ODT) formulation of frovatriptan aimed to make its oral administration easier and its dissolution faster than the commercial tablets, thus improving its effectiveness in migraine management.A screening D-optimal design was applied to investigate the effects of different levels of kind and amount of ODT special excipient and disintegrant agents (identified as the critical variables) on disintegration time (DT) and % drug dissolved at 30 s (%Diss), selected as the responses to optimize. The best excipients combination, emerged by the screening step, was in-depth investigated by a Response Surface Methodology.A design space was defined where every combination of the selected variables fulfilled the required values for the responses with P ≥ 95%. In particular, the optimized formulation (Pharmaburst® 60% and Na alginate 15%), showed DT = 1.62±0.08 s and %Diss= 9.02±0.47%, with good agreement between measured and calculated values. Moreover, the developed ODT complied with the USP uniformity weight and drug content requirements, exhibited proper hardness and low friability, and provided 100 % dissolved drug within 5 min.A frovatriptan ODT formulation was successfully developed by Quality by Design. It represents an effective alternative to conventional tablets, allowing easier oral administration (also to paediatric and geriatric people) and very faster drug dissolution, enhancing patient compliance and facilitating an earlier treatment of migraine attacks.

Shweta, Khan E., Tandon P., Bharti P., Kumar P., Maurya R.

In the present investigation, the natural product cearoin is studied by both experimental and theoretical methods. It is classified as a family of neoflavonoid and is widely used as a local anti-inflammatory, antibiotic, and antiallergic substance. To obtain detailed information about the discussed molecule, a number of experiments have been performed by various techniques including infrared, Raman, and ultraviolet–visible spectroscopy. Quantum chemical calculations were also performed for a clear interpretation and analysis of the results. HOMO–LUMO energy band gap gives a valuable understanding of the reactivity and some of the structural and physical properties of the theme molecule. Molecular electrostatic potential surface, global and local reactivity descriptors are used to study the chemical reactivity of the molecule. Natural bond orbital analysis is followed to figure out the stability of the molecule arising from hyperconjugative interactions and charge delocalization. As cearoin is utilized as an antibiotic material, molecular docking simulations have also been done on bacterial proteins to investigate the ligand–protein interaction.

Prajapati P., Pandey J., Shimpi M.R., Srivastava A., Tandon P., Velaga S.P., Sinha K.

Ezetimibe (EZT) is a hypocholesterolemic agent used for the treatment of elevated blood cholesterol levels as it lowers the blood cholesterol by blocking the absorption of cholesterol in intestine. Study aims to combine experimental and computational methods to provide insights into the structural and vibrational spectroscopic properties of EZT which is important for explaining drug substance physical and biological properties. Computational study on molecular properties of ezetimibe is presented using density functional theory (DFT) with B3LYP functional and 6-311++G(d,p) basis set. A detailed vibrational assignment has been done for the observed IR and Raman spectra of EZT. In addition to the conformational study, hydrogen bonding and molecular docking studies have been also performed. For conformational studies, the double well potential energy curves have been plotted for the rotation around the six flexible bonds of the molecule. UV absorption spectrum was examined in methanol solvent and compared with calculated one in solvent environment (IEF-PCM) using TD-DFT/6-31G basis set. HOMO-LUMO energy gap of both the conformers have also been calculated in order to predict its chemical reactivity and stability. The stability of the molecule was also examined by means of natural bond analysis (NBO) analysis. To account for the chemical reactivity and site selectivity of the molecules, molecular electrostatic potential (MEPS) map has been plotted. The combination of experimental and calculated results provide an insight into the structural and vibrational spectroscopic properties of EZT. In order to give an insight for the biological activity of EZT, molecular docking of EZT with protein NPC1L1 has been done.

Srivastava K., Srivastava A., Tandon P., Sinha K., Wang J.

Molecular structure and vibrational analysis of dipfluzine (C 27 H 29 FN 2 O) were presented using FT-IR and FT-Raman spectroscopy and quantum chemical calculations. The theoretical ground state geometry and electronic structure of dipfluzine are optimized by the DFT/B3LYP/6-311++G (d,p) method and compared with those of the crystal data. The 1D potential energy scan was performed by varying the dihedral angle using B3LYP functional at 6-31G(d,p) level of theory and thus the most stable conformer of the compound were determined. Molecular electrostatic potential surface (MEPS), frontier orbital analysis and electronic reactivity descriptor were used to predict the chemical reactivity of molecule. Energies of intra- and inter-molecular hydrogen bonds in molecule and their electronic aspects were investigated by natural bond orbital (NBO). To find out the anti-apoptotic activity of the title compound molecular docking studies have been performed against protein Fas.

Tortorella S., Talamo M.M., Cardone A., Pastore M., De Angelis F.

A systematic computational investigation on the optical properties of a group of novel benzofulvene derivatives (Martinelli 2014 Org. Lett. 16 3424-7), proposed as possible donor materials in small molecule organic photovoltaic (smOPV) devices, is presented. A benchmark evaluation against experimental results on the accuracy of different exchange and correlation functionals and semi-empirical methods in predicting both reliable ground state equilibrium geometries and electronic absorption spectra is carried out. The benchmark of the geometry optimization level indicated that the best agreement with x-ray data is achieved by using the B3LYP functional. Concerning the optical gap prediction, we found that, among the employed functionals, MPW1K provides the most accurate excitation energies over the entire set of benzofulvenes. Similarly reliable results were also obtained for range-separated hybrid functionals (CAM-B3LYP and wB97XD) and for global hybrid methods incorporating a large amount of non-local exchange (M06-2X and M06-HF). Density functional theory (DFT) hybrids with a moderate (about 20-30%) extent of Hartree-Fock exchange (HFexc) (PBE0, B3LYP and M06) were also found to deliver HOMO-LUMO energy gaps which compare well with the experimental absorption maxima, thus representing a valuable alternative for a prompt and predictive estimation of the optical gap. The possibility of using completely semi-empirical approaches (AM1/ZINDO) is also discussed.

Mary Y.S., Panicker C.Y., Thiemann T., Al-Azani M., Al-Saadi A.A., Van Alsenoy C., Raju K., War J.A., Srivastava S.K.

FT-IR and FT-Raman spectra of bis[(E)-anthranyl-9-acrylic]anhydride were recorded and analyzed. The conformational behavior is also investigated. The vibrational wave numbers were calculated using density functional theory (DFT) quantum chemical calculations. The data obtained from wave number calculations are used to assign vibrational bands obtained in Infrared and Raman spectra. Potential energy distribution was done using GAR2PED program. The geometrical parameters are compared with related structures. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using Natural Bonding Orbital (NBO) analysis. The Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) analysis are used to determine the charge transfer within the molecule. Molecular Electrostatic Potential (MEP) was performed by the DFT method. The calculated first hyperpolarizability of the title compound is comparable with the reported values of similar derivatives and is 4.23 times that of the standard nonlinear optical (NLO) material urea and the title compound and its derivatives are an attractive object for future studies of nonlinear optical properties. To evaluate the in silico antitumor activity of the title compound molecular docking studies were carried out against protein Bcl-xL. The (1)H-NMR spectrum is also reported.

Khan E., Shukla A., Srivastava A., Shweta S., Tandon P.

The optimized structure and active sites of ampicillin trihydrate calculated using monomeric and dimeric models.

Kumru M., Küçük V., Kocademir M., Alfanda H.M., Altun A., Sarı L.

Spectroscopic properties of quinoline-7-carboxaldehyde (Q7C) have been studied in detail both experimentally and theoretically. The FT-IR (4000-50 cm(-1)), FT-Raman (4000-50 cm(-1)), dispersive-Raman (3500-50 cm(-1)), and UV-Vis (200-400 nm) spectra of Q7C were recorded at room temperature (25 °C). Geometry parameters, potential energy surface about CCH(O) bond, harmonic vibrational frequencies, IR and Raman intensities, UV-Vis spectrum, and thermodynamic characteristics (at 298.15K) of Q7C were computed at Hartree-Fock (HF) and density functional B3LYP levels employing the 6-311++G(d,p) basis set. Frontier molecular orbitals, molecular electrostatic potential, and Mulliken charge analyses of Q7C have also been performed. Q7C has two stable conformers that are energetically very close to each other with slight preference to the conformer that has oxygen atom of the aldehyde away from the nitrogen atom of the quinoline.

Choudhary N., Agarwal P., Gupta A., Tandon P.

The molecular structural parameters, thermodynamic properties and vibrational frequencies of the fundamental modes of 2,2-dichloro- N -(2,3-dichlorophenyl) acetamide (2,3CPA) and 2,2-dichloro- N -(2,4-dichlorophenyl) acetamide (2,4CPA) have been obtained using density functional theory (DFT) technique in the B3LYP approximation and 6-311G(d,p) basis set. Detailed vibrational assignments of the observed FTIR and FT Raman bands have been proposed on the basis of potential energy distribution (PED). Most of the modes have wavenumbers in the expected range. The molecular electrostatic potential has been mapped primarily for predicting sites and relative reactivities towards electrophilic and nucleophilic attack. The atomic charges, electronic exchange interaction and charge delocalization of the molecule have been studied by natural bond orbital (NBO) analysis. Absorption wavelengths and their assignments in UV–vis region have been predicted, based on time-dependent density functional theory (TD-DFT) calculations. The temperature dependence of thermodynamic properties has been analyzed. Global and local reactivity descriptors have been calculated in order to have a deep insight into the molecule for further applications.

Srivastava A., Rawat P., Tandon P., Singh R.N.

Bicuculline – a plant alkaloid is an important molecule of current pharmaceutical interest. It is a competitive antagonist of γ-aminobutyric acid (GABA), particularly of GABAA receptor activation. The antagonistic behavior of BIC with GABAA receptor has been evaluated with the help of quantum chemical calculations. The equilibrium structures of bicuculline conformers have been obtained by geometry optimizations using density functional theory (DFT) calculations at the B3LYP/6-311G(d,p) level of theory. The conformational flexibility of bicuculline has been investigated because of its importance as an apparently specific antagonist of the neurotransmitter GABA. Dipole moment and first hyperpolarizability analysis of BIC have also been performed. For predicting inhibitor properties of BIC, the specific site of interaction of BIC with GABA receptor has been calculated with the help of global and local reactivity descriptors using DFT. Condensed Fukui functions, relative nucleophilicity and electrophilicity indices of BIC and GABA receptor for electrophilic or nucleophilic attack, are computed and compared with the HOMO and LUMO densities, integrated over the Hirshfeld atoms in molecules.

Singh P.S., Priyanka N., Devi T.J., Devi T.G.

Badran A., Ibrahim M.A., Hussain Z., Hassanin N.M.

Kumaran S., Sakthivel S., Rajesh R., Javed S., Vetrivelan V.

Parlak C., Alver Ö.

Paneru T.R., Joshi B.D., Tandon P., Vidal L.M., Ayala A.P.

Manikandan P., Kumar M., Kaleeswaran S., S.Chithra, Swarnamughi P., Nikpassand M., Prakash J.U.

Sabeg Y., Benali-Cherif R., Falek W., Takouachet R., Golea L., Aygün M., Benali-Cherif N.

Nivetha G.F., Srinivasan M., Mohan M., Brito K.K., Gokulapriya B., Selvapandiyan M., Vetrivelan V., Prasath M.

KK V., Bodke Y.D., Shivakumar N., Dalimba U.

AbstractIn this work, we reported the synthesis of a novel series of isatin‐incorporated thiazolyl‐coumarin derivatives 4(a–h) by a one‐pot three‐component reaction of substituted isatin, thiosemicarbazide, and 3‐(2‐bromoacetyl) coumarin. The structures of the coumarin‐thiazole scaffolds were precisely established by their IR, NMR, and HRMS spectral data. The UV–Vis absorption study of target molecules was investigated in six different solvents. Geometrical optimization, molecular electrostatic potential regions, and quantum chemical parameters were assessed using density functional theory (DFT) to explore the electronic properties of thiazolyl‐coumarin derivatives. The synthesized compounds were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis; all derivatives exhibited excellent antitubercular efficacy with MIC ≤ 3.25 µg/mL; among them, 4c and 4f were the most potent with a MIC of 1.56 µg/mL. Furthermore, in silico molecular docking analyses against the enoyl‐ACP reductase (InhA) enzyme were conducted; all target ligands demonstrated favorable binding interactions within the active site of the InhA enzyme.

Latif W., Hanan M., Jaffar A., Shafique A., Aziz S., Ateeq-Ur-Rehman, Kamran K., Iqbal J., Hina M., Mahr M.S.

Paneru T.R., Chaudhary M.K., Tandon P., Joshi B.D., Bezerra B.P., Ayala A.P.

Das A., Guha S., Halder A., Gharami S., Naskar R., Das G., Mondal T.K.

In vitro cytotoxicity of the synthesized Re(i)-carbonyl complexes (1/2) has been explored towards human-breast epithelial adenocarcinoma cell lines (MCF-7) and human breast epithelial cell lines (MCF-10A).

Kumaran M., Sivaranjani T., Suresh S., Periandy S., Soundhariya S., Alibrahim K.A., Alodhayb A.N.

The objective of this investigation is to learn more about the structural, electrical, spectroscopic, and physiochemical characteristics of biologically active cyano-4'-hydroxybiphenyl (CHBP). The title molecule's optimized conformational analysis was computed using the DFT/B3LYP/6-311++G (d, p) level of theory. The observed wavenumbers were compared with theoretical FT-IR and FT-Raman spectra.

Manogaran K., Sivaranjani T., Sengeny P., Venkatachalapathy V.S., Mahadevan M., Elangovan K., Armaković S., Armaković S.J., Abramović B.F.

The molecule of 2-Biphenyl Carboxylic Acid (2BCA), which contains peculiar features, was explored making use of density functional theory (DFT) and experimental approaches in the area of quantum computational research. The optimised structure, atomic charges, vibrational frequencies, electrical properties, electrostatic potential surface (ESP), natural bond orbital analysis and potential energy surface (PES) were obtained applying the B3LYP approach with the 6-311++ G (d,p) basis set.. The 2BCA molecule was examined for possible conformers using a PES scan. The methods applied for spectral analyses included FT-IR, FT-RAMAN, NMR, and UV-Vis results. Vibrational frequencies for all typical modes of vibration were found using the Potential Energy Distribution (PED) data. The UV-Vis spectrum was simulated using the TD-DFT technique, which is also seen empirically. The Gauge-Invariant Atomic Orbital (GIAO) approach was employed to model and study the

Dhlamini K.S., Selepe C.T., Ramalapa B., Cele Z., Malatji K., Govender K.K., Tshweu L., Ray S.S.

N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC), a quaternized chitosan derivative, has been shown to exhibit a broad spectrum of antimicrobial activity, especially against bacteria and enveloped viruses. Despite this, molecular docking studies showing its atomic-level mechanisms against these microorganisms are scarce. Here, for the first time, we employed molecular docking analyses to investigate the potential antibacterial activity of HTCC against Staphylococcus aureus and its antiviral activity against human immunodeficiency virus 1 (HIV-1). According to the findings, HTCC exhibited promising antibacterial activity with high binding affinities; however, it had limited antiviral activity. To validate these theoretical outcomes, experimental studies were conducted. Different derivatives of HTCC were synthesized and characterized using NMR, XRD, FTIR, and DLS. The in vitro assays validated the potent antibacterial efficacy of HTCC against S. aureus, whereas the antiviral studies did not show good antiviral activity. However, our research also revealed a promising avenue for further exploration of the antimicrobial activity of HTCC nanoparticles (NPs), since, thus far, no studies have been conducted to show the antiviral activity of HTCC NPs against HIV-1. The nanosized HTCC exhibited superior antiviral performance compared to the parent polymers, with complete (100%) inhibition of HIV-1 viral activity at the highest tested concentration (0.33 mg/mL).