Comparable Binding Energies Research Articles

Computational identification of natural product inhibitors against EGFR double mutant (T790M/L858R) by integrating ADMET, machine learning, molecular docking and a dynamics approach.

Double mutated epidermal growth factor receptor is a clinically important target for addressing drug resistance in lung cancer treatment. Therefore, discovering new inhibitors against the T790M/L858R (TMLR) resistant mutation is ongoing globally. In the present study, nearly 150 000 molecules from various natural product libraries were screened by employing different ligand and structure-based techniques. Initially, the library was filtered to identify drug-like molecules, which were subjected to a machine learning based classification model to identify molecules with a higher probability of having anti-cancer activity. Simultaneously, rules for constrained docking were derived from three-dimensional protein–ligand complexes and thereafter, constrained docking was undertaken, followed by HYDE binding affinity assessment. As a result, three molecules that resemble interactions similar to the co-crystallized complex were selected and subjected to 100 ns molecular dynamics simulation for stability analysis. The interaction analysis for the 100 ns simulation period showed that the leads exhibit the conserved hydrogen bond interaction with Gln791 and Met793 as in the co-crystal ligand. Also, the study indicated that Y-shaped molecules are preferred in the binding pocket as it enables them to occupy both pockets. The MMGBSA binding energy calculations revealed that the molecules have comparable binding energy to the native ligand. The present study has enabled the identification of a few ADMET adherent leads from natural products that exhibit the potential to inhibit the double mutated drug-resistant EGFR.

Solvent-Dependent Spectral Properties in Diverse Solvents, Light Harvesting and Antiviral Properties of Mono-Azo Dye (Direct Yellow-27): A Combined Experimental and Theoretical Study

In this paper, we have discussed for the first time a detailed electronic absorption study of the mono-azo dye Direct Yellow 27 [C[Formula: see text]H[Formula: see text]N4Na2O9S3] (DY-27) with five different homogeneous media by applying experimental and theoretical techniques along with some new characteristics of DY-27 in the field of solar cells as well as antiviral activities. A clear absorption band in the UV-visible region was observed, although the absorption maxima lie in the visible region. The electronic absorption transitions observed in our study were fully spin and symmetry allowed transitions with [Formula: see text]–[Formula: see text] character. Time-dependent density functional theory (TD-DFT) analysis has been done for understanding the electronic and the charge transfer performance. Moreover, the impacts of polar protic and polar aprotic solvents in the structural variation of DY-27 have been reported here. Further, applications of the dye in the field of solar cell, as well as antiviral activity, were performed using molecular modeling approaches. The dye exhibited a D–[Formula: see text]–A–A structure with a high light-harvesting efficiency (LHE) and good injection efficiency acts as an effective dye sensitized solar cell (DSSC). Molecular docking studies of the dye DY-27 performed with M-protease of the different corona viruses, MERS, SARS-CoV-1 and SARS-CoV-2 indicated comparable binding energies with the controlled inhibitors and best interactions are observed for the SARS-CoV-1.

Methane Adsorption on Heteroatom-Modified Maquettes of Porous Carbon Surfaces.

Experimental and theoretical studies disagree on the energetics of methane adsorption on carbon materials. However, this information is critical for the rational design and optimization of the structure and composition of adsorbents for natural gas storage. The delicate nature of dispersion interactions, polarization of both the adsorbent and the adsorbate, interplay between H-bonding and tetrel bonding, and induced dipole/Coulomb interactions inherent to methane physisorption require computational treatment at the highest possible level of theory. In this study, we employed the smallest reasonable computational model, a maquette of porous carbon surfaces with a central site for substitution and methane binding. The most accurate predictions of methane adsorption energetics were achieved by electron-correlated molecular orbital theory CCSD(T) and hybrid density functional theory MN15 calculations employing a saturated, all-electron basis set. The characteristic geometry of methane adsorption on a carbon surface ("lander approach") arises due to bonding interactions of the adsorbent π-system with the proximal H-C bonds of methane, in addition to tetrel bonding between the antibonding orbital of the distal C-H bond and the central atom of the maquette (C, B, or N). The polarization of the electron density, structural deformations, and the comprehensive energetic analysis clearly indicate a ∼3 kJ mol-1 preference for methane binding on the N-substituted maquette. The B-substituted maquette showed a comparable or lower binding energy than the unsubstituted, pure C model, depending on the level of theory employed. The calculated thermodynamic results indicate a strategy for incorporating electron-enriched substitutions (e.g., N) into carbon materials as a way to increase methane storage capacity over electron-deficient (e.g., B) modifications. The thermochemical analysis was revised for establishing a conceptual agreement between the experimental isosteric heat of adsorption and the binding enthalpies from statistical thermodynamics principles.

Prediction of the Drug–Target Binding Kinetics for Flexible Proteins by Comparative Binding Energy Analysis

There is growing consensus that the optimization of the kinetic parameters for drug-protein binding leads to improved drug efficacy. Therefore, computational methods have been developed to predict kinetic rates and to derive quantitative structure-kinetic relationships (QSKRs). Many of these methods are based on crystal structures of ligand-protein complexes. However, a drawback is that each ligand-protein complex is usually treated as having a single structure. Here, we present a modification of COMparative BINding Energy (COMBINE) analysis, which uses the structures of ligand-protein complexes to predict binding parameters. We introduce the option of using multiple structures to describe each ligand-protein complex in COMBINE analysis and apply this to study the effects of protein flexibility on the derivation of dissociation rate constants (koff) for inhibitors of p38 mitogen-activated protein (MAP) kinase, which has a flexible binding site. Multiple structures were obtained for each ligand-protein complex by performing docking to an ensemble of protein configurations obtained from molecular dynamics simulations. Coefficients to scale ligand-protein interaction energies determined from energy-minimized structures of ligand-protein complexes were obtained by partial least squares regression, and they allowed for the computation of koff values. The QSKR model obtained using single, energy-minimized crystal structures for each ligand-protein complex had higher predictive power than the QSKR model obtained with multiple structures from ensemble docking. However, incorporation of ligand-protein flexibility helped to highlight additional ligand-protein interactions that lead to longer residence times, such as interactions with residues Arg67 and Asp168, which are close to the ligand in many crystal structures. These results show that COMBINE analysis is a promising method to guide the design of compounds that bind to flexible proteins with improved binding kinetics.

Ameliorative role of ellagic acid against acute liver steatosis in adult zebrafish experimental model

Non-alcoholic fatty liver disease (NAFLD), also known as hepatic steatosis, is highly prevalent in developed countries despite advancements in clinical modalities. Therefore, there is a need for identifying the bioactive molecular entity (BME) that can therapeutically intervene with liver steatosis progression. In this study, we investigated the efficacy of one such BME - ellagic acid (EA) to ascertain its molecular therapeutic potential against iodoacetamide (IAA) mediated liver steatosis in an adult zebrafish model. Dysregulation of lipid homeostasis by IAA and its amelioration by EA was examined by histological staining and biochemical analysis in the adult zebrafish model. Furthermore, the gene expression analysis of 3-hydroxy methyl glutaryl (HMG) CoA reductase, fatty acid synthase and sterol receptor binding protein-1c in IAA mediated liver steatosis and its regulation by EA was also studied by reverse transcription-polymerase chain reaction (RT-PCR). Concurrently, the drug likeliness and pharmacokinetic properties of EA in comparison to Simvastatin (SIM) were analysed computationally by absorption, distribution, metabolism, and excretion (ADME) analysis. Also, the atomic level interactions of HMG-CoA reductase binding pocket with EA in comparison to SIM were examined by the molecular docking approach to ascertain their comparative binding energy (ΔG) and binding pose. Molecular docking revealed prominent hotspot residues (Gly 765, Gln 766, Asp 767, Gly 808) key to both EA and SIM interaction. All the above results revealed that the experimental observations wherein good agreement with the computational analysis substantiating the promising therapeutic potential of EA against IAA mediated liver steatosis.

Mechanistic selectivity investigation and 2D-QSAR study of some new antiproliferative pyrazoles and pyrazolopyridines as potential CDK2 inhibitors.

Novel series of diphenyl-1H-pyrazoles (4a-g) and pyrazolo[3,4-b]pyridines (5a-g and 7a-i) were synthesized and evaluated for their antiproliferative activity against breast cancer cell line (MCF7) and Hepatocellular carcinoma cell line (HepG2). The highest MCF7 growth inhibition activity was attained via compounds 4f and 7e (IC50=1.29 and 0.93μM, respectively), while compounds 5b and 7f were the most active ones against HepG2 (IC50=1.57 and 1.33μM, respectively) compared to doxorubicin (IC50=1.88 and 7.30μM, respectively). Cell cycle analysis showed arrest at S and G2-M phases in MCF7 cells treated with 4f and 7e, and at G2-M and G1/S phases in HepG2 cells treated with 5b and 7f, respectively. Apoptotic effect of compounds 4f, 5b, 7e, and 7f was indicated via their pre-G1 early and late apoptotic effects and augmented levels of caspase-9/MCF7 and caspase-3/HepG2. A worthy safety profile was assessed for compounds 4f and 7e on MCF10A and compounds 5b and 7f on THLE2 treated normal cells. Furthermore, compounds 4f, 5b and 7f displayed a promising selective profile for CDK2 inhibition vs. CDK1, CDK4, and CDK7 isoforms as proved from their selectivity index. Docking in CDK2 ATP binding site, co-crystallized with R-Roscovitine, demonstrated analogous interactions and comparable binding energy with the native ligand. 2D QSAR sighted the possible structural features governing the CDK2 inhibition activity elicited by the studied pyrazolo[3,4-b]pyridines. These findings present compounds 4f, 5b, and 7f as selective CDK2 inhibitors with promising antiproliferative activity against MCF7 and HepG2 cancer cells.

N,N′-dialkyl-2-thiobarbituric acid based sulfonamides as potential SARS-CoV-2 main protease inhibitors

An efficient methodology was developed to generate novel N,N′-dialkyl-2-thiobarbituric acid based sulfonamides S1–S4 in good to excellent yields (84%–95%). The synthesized compounds S1–S4 were docked to screen their in silico activities against two enzymes i.e., SARS-CoV-2 main protease enzyme with unliganded active site (2019-nCoV, coronavirus disease 2019, COVID-19) PDB ID: 6Y84 and SARS-CoV-2 Mpro PDB ID: 6LU7. Furthermore, some in silico physicochemical and physicokinetic properties were evaluated using the OSIRIS Property Explorer, Molinspiration property calculator, ADMET property calculator, and GUSAR to assess these compounds as potential candidates as lead compounds for the quest of SARS-CoV-2 main protease inhibitors. Molecular docking analyses of the synthesized compounds predicted that compound S3 is more potent as SARS-CoV-2 main protease inhibitor with binding energy –11.65 kcal/mol in comparison with reference inhibitor N3 (–10.95 kcal/mol), whereas compounds S1, S2, and S4 recorded comparable binding energies –9.89, –10.84, and –10.94 kcal/mol with reference inhibitor N3, which were much better than remdesivir (–9.85 kcal/mol). In case of SARS-CoV-2 Mpro, all compounds S1–S4 with docking energy values of –7.28, –8.38, –8.31, and –7.34 kcal/mol, respectively, were found to be potent in comparison with reference inhibitor N3 (–6.31 kcal/mol) and remdesivir (–6.33 kcal/mol). Ligand efficiency values against the target SARS-CoV-2 proteins, as well as α-glucosidase and DNA-(apurinic or apyrimidinic site) lyase inhibition results of these newly synthesized compounds, were also found to be promising.

Preliminary Identification of Hamamelitannin and Rosmarinic Acid as COVID-19 Inhibitors Based on Molecular Docking

Background: Recently, novel coronavirus disease, COVID-19 caused the outbreak situation of global public health. In this pandemic situation, all the people's lives of 212 Countries and Territories have been affected due to partial or complete lockdown and also as a result of mandatory isolations or quarantines. This is due to the non-availability of any secure vaccine. Objective: The present study helps us to identify and screen the best phytochemicals as potent inhibitors against COVID-19. Methods: In this paper, we choose two standard drugs namely hamamelitannin and rosmarinic acid as a probable inhibitor of pandemic COVID-19 receptor as compared to antimalarial drugs hydroxychloroquine, anti-viral drug remdesivir, and also baricitinib. This study was done by taking into consideration of molecular docking study, performed with Auto Dock 4.0 (AD4.0). All chemical structures were optimized with the Avogadro suite by applying the MMFF94 force field and also hamamelitannin, rosmarinic acid was optimized using the Gaussian G16 suite of UB3LYP/6- 311++G(d,p) basis set. Protein-ligand interaction was visualized by PyMOL software. Results: This work has provided an insightful understanding of protein-ligand interaction of hamamelitannin and rosmarinic acid showing comparable binding energies than that of clinically applying probable COVID-19 inhibitors hydroxychloroquine (an anti-malarial drug) and remdesivir (an anti-viral drug). Conclusions: We will expect that if its anti-SARS-CoV-2 activity is validated in human clinical trials, these two drugs may be developed as an effective antiviral therapeutics towards infected patients in this outbreak and pandemic situation of COVID-19.

The anti-HCV, Sofosbuvir, versus the anti-EBOV Remdesivir against SARS-CoV-2 RNA dependent RNA polymerase in silico.

Coronavirus diseases 2019 (COVID-19) are seriously affecting human health all over the world. Nucleotide inhibitors have promising results in terms of its efficacy against different viral polymerases. In this study, detailed molecular docking and dynamics simulations are used to evaluate the binding affinity of a clinically approved drug, sofosbuvir, with the solved structure of the viral protein RNA-dependent RNA polymerase (RdRp) and compare it to the clinically approved drug, Remdesivir. These drugs are docked onto the three-dimensional structure of the nsp12 protein of SARS-CoV-2, which controls the polymerization process. Hence, it is considered one of the primary therapeutic targets for coronaviruses. Sofosbuvir is a drug that is currently used for HCV treatment; therefore, HCV RdRp is used as a positive control protein target. The protein dynamics are simulated for 100 ns, while the binding is tested during different dynamics states of the SARS-CoV-2 RdRp. Additionally, the drug-protein complexes are further simulated for 20 ns to explore the binding mechanism. The interaction of SARS-CoV-2 RdRp as a target with the active form of sofosbuvir as a ligand demonstrates binding effectiveness. One of the FDA-approved antiviral drugs, such as sofosbuvir, can help us in this mission, aiming to limit the danger of COVID-19. Sofosbuvir was found to bind nsp12 with comparable binding energies to that of Remdesivir, which has been reported for its potential against COVID-19 RdRp and is currently approved by the FDA.Graphic abstract

Design and Characterisation of Inhibitory Peptides against Bleg1_2478, an Evolutionary Divergent B3 Metallo-β-lactamase.

Previously, a hypothetical protein (HP) termed Bleg1_2437 (currently named Bleg1_2478) from Bacillus lehensis G1 was discovered to be an evolutionary divergent B3 subclass metallo-β-lactamase (MBL). Due to the scarcity of clinical inhibitors for B3 MBLs and the divergent nature of Bleg1_2478, this study aimed to design and characterise peptides as inhibitors against Bleg1_2478. Through in silico docking, RSWPWH and SSWWDR peptides with comparable binding energy to ampicillin were obtained. In vitro assay results showed RSWPWH and SSWWDR inhibited the activity of Bleg1_2478 by 50% at concentrations as low as 0.90 µM and 0.50 µM, respectively. At 10 µM of RSWPWH and 20 µM of SSWWDR, the activity of Bleg1_2478 was almost completely inhibited. Isothermal titration calorimetry (ITC) analyses showed slightly improved binding properties of the peptides compared to ampicillin. Docked peptide–protein complexes revealed that RSWPWH bound near the vicinity of the Bleg1_2478 active site while SSWWDR bound at the center of the active site itself. We postulate that the peptides caused the inhibition of Bleg1_2478 by reducing or blocking the accessibility of its active site from ampicillin, thus hampering its catalytic function.

Dynamic polaronic screening for anomalous exciton spin relaxation in two-dimensional lead halide perovskites.

Two-dimensional lead halide perovskites with confined excitons have shown exciting potentials in optoelectronic applications. It is intriguing but unclear how the soft and polar lattice redefines excitons in layered perovskites. Here, we reveal the intrinsic exciton properties by investigating exciton spin dynamics, which provides a sensitive probe to exciton coulomb interactions. Compared to transition metal dichalcogenides with comparable exciton binding energy, we observe orders of magnitude smaller exciton-exciton interaction and, counterintuitively, longer exciton spin lifetime at higher temperature. The anomalous spin dynamics implies that excitons exist as exciton polarons with substantially weakened inter- and intra-excitonic interactions by dynamic polaronic screening. The combination of strong light matter interaction from reduced dielectric screening and weakened inter-/intra-exciton interaction from dynamic polaronic screening explains their exceptional performance and provides new rules for quantum-confined optoelectronic and spintronic systems.

Evaluation of acridinedione analogs as potential SARS-CoV-2 main protease inhibitors and their comparison with repurposed anti-viral drugs

BackgroundThe main protease (Mpro) of SARS-CoV-2 is involved in the processing of vital polypeptides required for viral genome replication and transcription and is one of the best-characterized targets to inhibit the progression of SARS-CoV-2 in infected individuals. MethodsWe screened a set of novel classes of acridinediones molecules to efficiently bind and inhibit the activity of the SARS-CoV-2 by targeting the Mpro. The repurposed FDA-approved antivirals were taken as standard molecules for this study. Long term (1.1 μs) MD simulations were performed to analyze the conformational space of the binding pocket of Mpro bound to the selected molecules. ResultsThe molecules DSPD-2 and DSPD-6 showed more favorable MM-PBSA interaction energies and were seated more deeply inside the binding pocket of Mpro than the topmost antiviral drug (Saquinavir). Moreover, DSPD-5 also exhibited comparable binding energy to Saquinavir. The analysis of per residue contribution energy and SASA studies indicated that the molecules showed efficient binding by targeting the S1 subsite of the Mpro binding pocket. ConclusionThe DSPD-2, DSPD-6, and DSPD-5 could be developed as potential inhibitors of SARS-CoV-2. Moreover, we suggest that targeting molecules to bind effectively to the S1 subsite could potentially increase the binding of molecules to the SARS-CoV-2 Mpro.

Investigating the molecular mechanism of hydroxylated bromdiphenyl ethers to inhibit the thyroid hormone sulfotransferase SULT1A1

Hydroxylated bromodiphenyl ethers (OH-BDEs) have raised great concern due to their potential endocrine disrupting effects on humans. In vitro experiments have indicated OH-BDEs can inhibit the activity of thyroid hormone (TH) sulfotransferases (SULTs); however, the molecular mechanism has not been investigated in depth. In this work, we employed 17 OH-BDEs with five or fewer Br atoms, and performed integrated computational simulations to unravel the possible inhibition mechanism of OH-BDEs on human SULT1A1. The molecular docking results demonstrate that OH-BDEs form hydrogen bonds with residues Lys106 and His108, and the neutral OH-BDEs show comparable binding energies with their anionic counterparts. The further hybrid quantum mechanical/molecular mechanical (QM/MM) calculations unravel a metabolic mechanism of OH-BDEs comprised by proton abstraction and sulfation steps. This mechanism is involved in the SULT1A1 inhibition by some OH-BDEs comprised of three or fewer Br atoms, while other OH-BDEs likely only form ternary complexes to competitively inhibit SULT1A1 activity. Moreover, the effect of the hydroxyl group of OH-BDEs on SULT1A1 inhibition potential follows the order of ortho-OH BDE > meta-OH BDE > para-OH BDE. These results provide an insight into the inhibition mechanism of OH-BDEs to SULT1A1 at the molecular level, which are beneficial in illuminating the molecular initiating events involved in the TH disruption of OH-BDEs.

Molecular engineering of A–D–C–D–A configured small molecular acceptors (SMAs) with promising photovoltaic properties for high-efficiency fullerene-free organic solar cells

Non fullerene small acceptor molecules in organic photovoltaics are proven beneficial than the traditional fullerene based acceptors for their fine contribution in organic solar cells. Researchers are constantly doing efforts for designing novel acceptor materials with promising photovoltaic properties. Designing of novel molecules by end-capped modifications is a convenient strategy to obtain high efficiency acceptor molecules for OSCs. Herein, we studied optoelectronic characteristics of five novel acceptor–donor–core–donor–acceptor configured small acceptor molecules (S1–S5) after end-capped modifications of recently synthesized DF-PCIC molecule. Designed molecules S1–S5 consist of 1,4-difluorobenzene (as central core), 4,4-bis(2-ethylhexyl)-2,6-dimethyl-4H-cyclopenta[1,2-b:5,4-b′]dithiophene as donor which directly attached with different end-capped acceptors. The electronic and optical properties of newly designed (S1–S5) molecules are examined and compared with reference molecule with the aid of DFT and TD-DFT. Certain key parameters like frontier molecular orbitals analysis, density of states, dipole moment, binding energy along with transition density matrix, excitation energy, charge mobility, absorption maxima and charge transfer analysis have been performed in order to explore the photo-physical, optoelectronic and photovoltaic properties of designed and reference molecule. Out of newly designed structures, S4 displayed lowest energy band-gap (2.25 eV) with red-shifting in absorption spectrum (λmax = 712.43 nm) in chloroform which disclosed the perfect relationship between end-capped acceptor with large electron withdrawing character through extended conjugation. Similarly, S1 exhibited highest value (1.53 V) of open circuit voltage (Voc) with respect to PTB7-Th donor material owing to lower values of λe. Designed molecules exhibit better electron and hole mobility as compared to reference molecule R. All molecules express better absorption maximum, open circuit voltage, low excitation energies, comparable binding energies, large dipole moment and efficient electron and hole transport as compared to reference molecules. So, results these parameters suggest that end-capped modification is a convenient strategy in order to enhance the efficiency of OSCs. Therefore, conceptualized molecules are recommended to experimentalist for out-looking future developments of highly efficient solar cells.

Synthesis, Characterization, and Molecular Docking Studies of N-Acylated Butyro and Valerolactam Derivatives with Antiproliferative and Cytotoxic Activities

Background: Electrophilic compounds bearing Michael acceptors present great promise in anticancer drug discovery. Methods: Drawing inspirations from cytotoxic Piper lactam alkaloids, twelve N-acylated butyro- and valerolactams were prepared and evaluated for antiproliferative and cytotoxic activities against the normal human umbilical vein endothelial cells (HUVEC), chronic human myeloid leukemia cells (K- 562), and Henrietta Lacks (HeLa) cells used as model cell lines. Molecular docking of bioactive derivatives was performed against tyrosine kinase. Results: Results of the MTT assay showed the crotonylated (5) and nitro-containing cinnamoyl (8) butyrolactams, and, the crotonylated (10), trifluoromethylated (13), and chlorinated (14) cinnamoyl valerolactam derivatives as the most antiproliferative against human myeloid leukemia cells. The trifluoromethylated cinnamoyl valerolactam (13) displayed the best selectivity on K-562 cells. Molecular docking studies of 13 against tyrosine kinase provided evidence as tyrosine kinase inhibitor, having comparable binding energy and receptor interaction with imatinib. Conclusion: The presence of electrophilic N-acrylic moieties contributes to the potential of a compound as inspiration to develop anti-leukemia drugs.

Structural and electronic properties of 2H phase Janus transition metal dichalcogenide bilayers

In this paper, we systematically investigate the structural and electronic properties of Janus transition metal dichalcogenide bilayers using first-principles calculations. 2H phase Janus MXY (M = Mo, W; X, Y=S, Se, Te) bilayers with five possible stacking types are focused. The energetically favorable stacking type and the corresponding gap between layers are determined by comparing binding energies with van der Waals interaction. The Janus MXY bilayers with this specific stacking are indirect semiconductors with bandgaps ranging from 0.014 eV to 0.932 eV, which are smaller compared with their monolayers. The valence band maximums of MoSeTe, WSSe and WSeTe bilayers locate at high-symmetry K point while the conduction band minimums of all bilayers except MoSSe move to the position between K and Γ. Moreover, the electronic band structures of total 30 possible Janus TMD bilayers are demonstrated, presenting a promising platform for nanoscale electronic and optoelectronic devices.

Synthesis of a New Series of Furopyranone‐ and Furocoumarin‐Chromone Conjugates Followed by In–Vitro Cytotoxicity Activity Evaluation, and Molecular Docking Study

AbstractIn this work, new furopyranone‐ and furocoumarin‐chromone conjugates were successfully synthesized via the one‐pot three‐component condensation reactions of 3‐formylchromone derivatives, 4‐hydroxy‐6‐methylpyrone or 4‐hydroxycoumarin and alkyl or aryl isocyanides in refluxing toluene within 2 h. Molecular docking studies on cyclooxygenase enzymes (COX‐1, COX‐2) indicated that most derivatives have greater or moderate binding affinities than 3‐formylchromone which was used as a reference compound. Even some of the new products showed comparable binding energy towards the relative co‐crystalized ligand into COX‐1 and COX‐2. In general, all of the new products formed one to three hydrogen bonds with amino acid residues in the active site of both enzymes. Furthermore, the cytotoxicity activity of some selected compounds was investigated against human foreskin fibroblast cells (BJ) and human breast cancer cells (MDA‐MB‐231) using the MTT assay. All selected compounds exhibited significant cell growth inhibitory against cancerous cells with varied potencies when compared to 3‐formylchromone. However, they were much less toxic against normal cells.

Highly conserved hemagglutinin peptides of H1N1 influenza virus elicit immune response.

In the current study, two highly conserved (> 90%) H1N1 hemagglutinin peptides STDTVDTVLEKNVTVTHSVNL (H1) and KVNSVIEKMNTQFTAVGKEF (H2) containing multiple T-cell epitopes have been assessed for their immunogenic potential in vitro, subjecting peripheral blood mononuclear cells from healthy volunteers to repetitive stimulation of chemically synthesised H1 and H2 peptides, and measuring their interferon (IFN)-γ level (ELISA) and proliferation (MTT assay). Further, these peptides were analysed for their binding affinity with 18 different human leukocyte antigen (HLA) class I and II by means of molecular docking. All seven samples tested for H1- and H2-induced IFN-γ secretion were found to have enhanced IFN-γ production. Six (H1) and five (H2) samples have shown proliferative response compared to unstimulated cells. Peptide-induced IFN-γ secretion and proliferation in healthy samples represent the immunogenic potential of these peptides. Further, molecular docking results reveal that the peptides have comparable binding energy to that of native bound peptide for both HLA classes which indicates that these peptides have the capability to be presented by different HLA molecules required for T-cell response. Hence, these conserved immunogenic hemagglutinin peptides are potential candidates for influenza vaccine development.

Prediction of Drug-Target Binding Kinetics by Comparative Binding Energy Analysis.

A growing consensus is emerging that optimizing the drug–target affinity alone under equilibrium conditions does not necessarily translate into higher potency in vivo and that instead binding kinetic parameters should be optimized to ensure better efficacy. Therefore, in silico methods are needed to predict the kinetic parameters and the mechanistic determinants of drug–protein binding. Here we demonstrate the application of COMparative BINding Energy (COMBINE) analysis to derive quantitative structure–kinetics relationships (QSKRs) for the dissociation rate constants (koff) of inhibitors of heat shock protein 90 (HSP90) and HIV-1 protease. We derived protein-specific scoring functions by correlating koff rate constants with a subset of weighted interaction energy components determined from the energy-minimized structures of drug–protein complexes. As the QSKRs derived for these sets of chemically diverse compounds have good predictive ability and provide insights into important drug–protein interactions for optimizing koff, COMBINE analysis offers a promising approach for binding kinetics-guided lead optimization.

Identification of amentoflavone as a potent highly selective PARP-1 inhibitor and its potentiation on carboplatin in human non-small cell lung cancer

Nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in the repair of DNA and is a promising target in the development of chemosensitizers. This study first investigated the inhibitory effects of amentoflavone (AMF) and its derivatives on PARP-1 and the potentiation of AMF on carboplatin (CBP) in non-small cell lung cancer (NSCLC). This study aims to evaluate the inhibitory effect of AMF against PARP-1 and its potentiation on CBP in lung cancer both in vitro and in vivo. The inhibitory effect of AMF on PARP-1 was investigated using molecular docking and cell-free model of PARP-1 assay. Its potentiation on CBP in lung cancer was also evaluated. Fluorescence resonance energy transfer assay was used to detect the inhibitory effects of AMF and its analogues on PARP-1. Molecular docking was employed to predict the binding mode of AMF and PARP-1. MTT assay, isobologram analysis, Hoechst staining, and Annexin V-PI double staining were used to confirm the potentiation of AMF on CBP in vitro. siRNA (PARP-1)-A549 cells were used to reveal the action target of AMF. Western blot analysis, immunohistochemistry, and Tunnel assay were employed to evaluate the potentiation of AMF on CBP in A549 xenograft mice. AMF and its analogues exerted excellent inhibitory effects on PARP-1 with IC50 values ranging from 0.198 μM to 0.409 μM. Docking experiment showed that AMF can stably bind to PARP-1 with a comparable binding energy to olaparib. AMF can decrease the expression of PAR induced by H2O2in vitro. AMF synergistically increased the CBP anti-proliferative effect in A549. However, its potentiation nearly disappeared when the cells were transfected with siRNAs against PARP-1. Oral administration of AMF (100 mg/kg), combined with CBP, remarkably inhibited A549 tumor growth and ki67 expression, and increased apoptosis compared with CBP-alone group. All results suggest that AMF can be a potential PARP-1 inhibitor and a candidate adjuvant agent to boost the anticancer effect of CBP in NSCLC.