G-Protein Coupled Receptors: Experimental and Computational Approaches

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Exploring 3D structure of human gonadotropin hormone receptor at antagonist state using homology modeling, molecular dynamic simulation, and cross-docking studies

Human gonadotropin hormone receptor, a G-protein coupled receptor, is the target of many medications used in fertility disorders. Obtaining more structural information about the receptor could be useful in many studies related to drug design. In this study, the structure of human gonadotropin receptor was subjected to homology modeling studies and molecular dynamic simulation within a DPPC lipid bilayer for 100 ns. Several frames were thereafter extracted from simulation trajectories representing the receptor at different states. In order to find a proper model of the receptor at the antagonist state, all frames were subjected to cross-docking studies of some antagonists with known experimental values (Ki). Frame 194 revealed a reasonable correlation between docking calculated energy scores and experimental activity values (|r| = 0.91). The obtained correlation was validated by means of SSLR and showed the presence of no chance correlation for the obtained model. Different structural features reported for the receptor, such as two disulfide bridges and ionic lock between GLU90 and LYS 121 were also investigated in the final model. © 2016, Springer-Verlag Berlin Heidelberg

Molecular Docking and Thermodynamic Studies of the Interactions between Aspirinate Complexes of Transition metals and Cyclooxygenase-2 Enzyme: Quantum Chemical Calculations based on the ONIOM method

In the present research, molecular docking and thermodynamic properties of the transition metal complexes of aspirin were calculated against Cyclooxygenase-2 (COX-2) enzyme.  Density functional theory with dispersion function (DFT-D) using LANL2DZ basis set calculation was carried out to study the structural and thermodynamic properties of the interaction between aspirinate complexes of transition metals and COX-2. The ONIOM2 (wB97X-D/LANL2DZ:UFF) method was applied to the interaction of transition metal complexes with COX-2 binding site. The Interaction enthalpies and the Gibbs free energies between aspirinate complexes of Cu(II), Zn(II), Fe(III), and In(III) as anti-inflammatory complexes and COX-2  enzyme in the gas phase were calculated. The structure as well as the thermodynamics of optimized metal complexes was debated from the biological point of view. In the gas phase, the interaction was relatively strong and transition metal complexes could be used as potential anti-inflammatory drugs.</p

Pharmacy or PharmaNBIC: Thinking about 50 years ahead of pharmacy

The contemporary trends and concepts in pharmacy are widely affected by the emergence of Nano-, Bio- or Info- technologies (NBI) as an attempt to develop different principles of medicine. This commentary is trying to make a think tank room for 50 years ahead of pharmacy where the ambience of pharmacy will be affected by such technologies (NBI) together with cognition (NBIC) to achieve intelligence, low adverse reaction and holistic action medicals.   </p

Getting Ready for Large-Scale Proteomics in Crop Plants

Plants are an indispensable cornerstone of sustainable global food supply. While immense progress has been made in decoding the genomes of crops in recent decades, the composition of their proteomes, the entirety of all expressed proteins of a species, is virtually unknown. In contrast to the model plant Arabidopsis thaliana, proteomic analyses of crop plants have often been hindered by the presence of extreme concentrations of secondary metabolites such as pigments, phenolic compounds, lipids, carbohydrates or terpenes. As a consequence, crop proteomic experiments have, thus far, required individually optimized protein extraction protocols to obtain samples of acceptable quality for downstream analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). In this article, we present a universal protein extraction protocol originally developed for gel-based experiments and combined it with an automated single-pot solid-phase-enhanced sample preparation (SP3) protocol on a liquid handling robot to prepare high-quality samples for proteomic analysis of crop plants. We also report an automated offline peptide separation protocol and optimized micro-LC-MS/MS conditions that enables the identification and quantification of ~10,000 proteins from plant tissue within 6 h of instrument time. We illustrate the utility of the workflow by analyzing the proteomes of mature tomato fruits to an unprecedented depth. The data demonstrate the robustness of the approach which we propose for use in upcoming large-scale projects that aim to map crop tissue proteomes

Formulation, microscopic and instrumental fingerprinting analysis of a multi-ingredients traditional Persian medicine product, Coriander Triphala

Background and aims: Today, due to the increasing use of natural and traditional medicinal products, control and standardization of herbal and traditional medicinal products is very important. As most of the traditional medicinal plants are not scientifically validated, scientific evaluation along with traditional knowledge is essential to obtain effective drugs with significant control over the quality of the product for commercial purpose. In traditional Persian medicine, various forms of medicine including one or a combination of several drugs are mentioned. Coriander Triphala widely prescribed as a purgative, gastrointestinal and mental tonic. Despite the widespread use of this drug, no significant control or standardization and documented pharmacognosy studies have been performed on it. Therefore this study is developed for this purpose. Methods: In this study, the traditional form of Coriander Triphala was prepared based on the pharmaceutics points mentioned in traditional medicine texts and quality control and pharmacognostic studies were performed. The associated fingerprints were performed by gas chromatography–mass spectrometry (GC-MS), and then one of the main components of the product was determined by as gas chromatography-flame ionization detector (GC-FID). Results: The spectrum of essential oils of Coriander Triphala and Coriander had 59.19% and 75.34% linalool, respectively. The microbial assay showed no undesirable results. The IR spectrum of Coriander Triphala at first day and 40 days later differed by 2%. Conclusion: Standardization of the product using GC-FID indicates the presence of 0.172 μg linalool in 100 g the Coriander Triphala product. Keywords Traditional Persian medicine Coriander Triphala Linalool GC-MS GC-FI

Pharmacy or PharmaNBIC: Thinking about 50 years ahead of pharmacy today

The contemporary trends and concepts in pharmacy are widely affected by the emergence of Nano-, Bio- or Info- technologies (NBI) as an attempt to develop different principles of medicine. This commentary is trying to make a think tank room for 50 years ahead of today’s pharmacy, where the ambience of pharmacy will be affected by such technologies together with cognition (NBIC) to achieve intelligent, low adverse reaction and holistic action medicals

Theoretical investigation of cyclooxygenase inhibition property of several non-steroidal anti-inflammatory drugs by density functional theory calculations and molecular docking studies

Understanding the geometry and electronic properties of non-steroidal anti-inflammatory drugs (NSAIDs) and the nature of their interactions with human cyclooxygenase-2 (COX-2) is important in the development and design of novel NSAIDs. In this paper, B3LYP/6-311++G (d,p) level of theory was applied to assess the acidity of NSAIDs in the gas phase. Subsequently, the role of intramolecular hydrogen bond on acidity of these compounds was confirmed by means of natural bond orbital (NBO) and quantum theory of atoms in molecules analyses (QTAIM). Furthermore, by applying the polarized continuum model (PCM) at the B3LYP/6-311++G(d,p) level, the pKa value of NSAIDs in aqueous solution was calculated. The maximum error was found to be less than 0.1 pKa unit in comparison with the experimental value. This protocol can be used as a tool to predict pKa values of NSAIDs in future studies. In the last step, attempts have been made to generate a functional model of the structure of human COX-2 enzyme by means of homology modeling to gain more insight into the nature of interactions between NSAIDs and the active site of this COX-2 enzyme by docking studies. In addition, a mean binding energy for each drug was estimated based on its ionization ratio

De novo design of novel protease inhibitor candidates in the treatment of SARS-CoV-2 using deep learning, docking, and molecular dynamic simulations

The main protease of SARS-CoV-2 is a critical target for the design and development of antiviral drugs. 2.5 M compounds were used in this study to train an LSTM generative network via transfer learning in order to identify the four best candidates capable of inhibiting the main proteases in SARS-CoV-2. The network was fine-tuned over ten generations, with each generation resulting in higher binding affinity scores. The binding affinities and interactions between the selected candidates and the SARS-CoV-2 main protease are predicted using a molecular docking simulation using AutoDock Vina. The compounds selected have a strong interaction with the key MET 165 and Cys145 residues. Molecular dynamics (MD) simulations were run for 150ns to validate the docking results on the top four ligands. Additionally, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and hydrogen bond analysis strongly support these findings. Furthermore, the MM-PBSA free energy calculations revealed that these chemical molecules have stable and favorable energies, resulting in a strong binding with Mpro's binding site. This study's extensive computational and statistical analyses indicate that the selected candidates may be used as potential inhibitors against the SARS-CoV-2 in-silico environment. However, additional in-vitro, in-vivo, and clinical trials are required to demonstrate their true efficacy