Machine Learning-Assisted Computational Screening of Adhesive Molecules Derived from Dihydroxyphenyl Alanine.

Marine mussels adhere to virtually any surface via 3,4-dihydroxyphenyl-L-alanines (L-DOPA), an amino acid largely contained in their foot proteins. The biofriendly, water-repellent, and strong adhesion of L-DOPA are unparalleled by any synthetic adhesive. Inspired by this, we computationally designed diverse derivatives of DOPA and studied their potential as adhesives or coating materials. We used first-principles calculations to investigate the adsorption of the DOPA derivatives on graphite. The presence of an electron-withdrawing group, such as nitrogen dioxide, strengthens the adsorption by increasing the π-π interaction between DOPA and graphite. To quantify the distribution of electron charge and to gain insights into the charge distribution at interfaces, we performed Bader charge analysis and examined charge density difference plots. We developed a quantitative structure-property relationship (QSPR) model using an artificial neural network (ANN) to predict the adsorption energy. Using the three-dimensional and quantum mechanical electrostatic potential of a molecule as a descriptor, the present quantum NN model shows promising performance as a predictive QSPR model.

Development of novel chromones as antioxidant COX2 inhibitors: in vitro, QSAR, DFT, molecular docking, and molecular dynamics studies.

The chromone derivatives are playing a prominent role in many plant cycles, for instance, the regulation of growth, stimulation of oxygen uptake in plants, and essential food constituents with valuable pro-health properties. Determination of the antioxidant activity of these compounds is an interesting approach to drug design and development. The antioxidant activity of the novel fifteen chromone compounds was estimated by using a spectrophotometric Dichloro-5,6-dicyano 1,4-benzoquinone (DDQ) assay method and the mechanism of antioxidant activity was discussed based on the Density functional theory (DFT) calculations. The compounds showed significant antioxidant activity which was correlated to their molecular structure by considering various molecular descriptors. Further, by using regression analysis QSAR-modeled equation was proposed and it has shown a high correlation coefficient value (0.946. We perform molecular docking and molecular dynamics simulations against the cyclooxygenase (COX2) enzyme to investigate the molecule's anti-inflammatory activity and stability of protein-ligand complexes. Molecular docking and dynamics simulations revealed the compounds B3 and B8 were interacting with essential residues TYR385, HIS386, ASN382, TRP387, and HIS388 in the binding site that were crucial for optimizing heme and the resultant peroxidase and cyclooxygenase activities. The root mean square displacement and root mean square fluctuation plots revealed the stability of the B3-COX2 and B8-COX2 complexes. Based on our results, B3 and B8 compounds are considered as best antioxidants as well as COX2 inhibitors.Communicated by Ramaswamy H. Sarma.

Computer simulation approach to the identification of visfatin-derived angiogenic peptides.

Angiogenesis plays an essential role in various normal physiological processes, such as embryogenesis, tissue repair, and skin regeneration. Visfatin is a 52 kDa adipokine secreted by various tissues including adipocytes. It stimulates the expression of vascular endothelial growth factor (VEGF) and promotes angiogenesis. However, there are several issues in developing full-length visfatin as a therapeutic drug due to its high molecular weight. Therefore, the purpose of this study was to develop peptides, based on the active site of visfatin, with similar or superior angiogenic activity using computer simulation techniques.Initially, the active site domain (residues 181∼390) of visfatin was first truncated into small peptides using the overlapping technique. Subsequently, the 114 truncated small peptides were then subjected to molecular docking analysis using two docking programs (HADDOCK and GalaxyPepDock) to generate small peptides with the highest affinity for visfatin. Furthermore, molecular dynamics simulations (MD) were conducted to investigate the stability of the protein-ligand complexes by computing root mean square deviation (RSMD) and root mean square fluctuation(RMSF) plots for the visfatin-peptide complexes. Finally, peptides with the highest affinity were examined for angiogenic activities, such as cell migration, invasion, and tubule formation in human umbilical vein endothelial cells (HUVECs). Through the docking analysis of the 114 truncated peptides, we screened nine peptides with a high affinity for visfatin. Of these, we discovered two peptides (peptide-1: LEYKLHDFGY and peptide-2: EYKLHDFGYRGV) with the highest affinity for visfatin. In an in vitrostudy, these two peptides showed superior angiogenic activity compared to visfatin itself and stimulated mRNA expressions of visfatin and VEGF-A. These results show that the peptides generated by the protein-peptide docking simulation have a more efficient angiogenic activity than the original visfatin.

A Combination of Pharmacophore-Based Virtual Screening, Structure-Based Lead Optimization, and DFT Study for the Identification of S. epidermidis TcaR Inhibitors.

The transcriptional regulator (TcaR) enzyme plays an important role in biofilm formation. Prevention of TcaR-DNA complex formation leads to inhibit the biofilm formation is likely to reveal therapeutic ways for the treatment of bacterial infections. To identify the novel ligands for TcaR and to provide a new idea for drug design, two efficient drug design methods, such as pharmacophore modeling and structure-based drug design, were used for virtual screening of database and lead optimization, respectively. Gemifloxacin (FDA-approved drug) was considered to generate the pharmacophore model for virtual screening of the ZINC database, and five hits, namely ZINC77906236, ZINC09550296, ZINC77906466, ZINC09751390, and ZINC01269201, were identified as novel inhibitors of TcaR with better binding energies. Using structure-based drug design, a set of 7a-7p inhibitors of S. epidermidis were considered, and Mol34 was identified with good binding energy and high fitness score with improved pharmacological properties. The active site residues ARG110, ASN20, HIS42, ASN45, ALA38, VAL63, VAL68, ALA24, VAL43, ILE57, and ARG71 are playing a promising role in inhibition process. In addition, we performed DFT simulations of final hits to understand the electronic properties and their significant role in driving the inhibitor to adopt apposite bioactive conformations in the active site. Conclusively, the newly identified and designed hits from both the methods are promising inhibitors of TcaR, which can hinder biofilm formation.

Adenine-Based Zn(II)/Cd(II) Metal-Organic Frameworks as Efficient Heterogeneous Catalysts for Facile CO2 Fixation into Cyclic Carbonates: A DFT-Supported Study of the Reaction Mechanism.

We synthesized two new adenine-based Zn(II)/Cd(II) metal-organic frameworks (MOFs), namely, [Zn2(H2O)(stdb)2(5H-Ade)(9H-Ade)2]n (PNU-21) and [Cd2(Hstdb)(stdb)(8H-Ade)(Ade)]n (PNU-22), containing auxiliary dicarboxylate ligand (stdb = 4,4'-stilbenedicarboxylate). Both MOFs were characterized by multiple analytical techniques such as single-crystal X-ray diffraction (SXRD), powder X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis, scanning electron microscopy, as well as temperature program desorption and Brunauer-Emmett-Teller measurements. Both MOFs were structurally robust and possessed unsaturated Lewis acidic metal centers [Zn(II) and Cd(II)] and free basic N atoms of adenine molecules. They were used as heterogeneous catalysts for the fixation of CO2 into five-membered cyclic carbonates. Significant conversion of epichlorohydrin (ECH) was attained at a low CO2 pressure (0.4 MPa) and moderate catalyst (0.6 mol %)/cocatalyst (0.3 mol %) amounts, with over 99% selectivity toward the ECH carbonate. They showed comparable or even higher catalytic activity than other previously reported MOFs. Because of high thermal stability and robust architecture of PNU-21/PNU-22, both catalysts could be reused with simple separation up to five successive cycles without any considerable loss of their catalytic activity. Densely populated acidic and basic sites in both Zn(II)/Cd(II) MOFs facilitated the conversion of ECH to ECH carbonate in high yields. The reaction mechanism of the cycloaddition reaction between ECH and CO2 is described by possible intermediates, transition states, and pathways, from the density functional theory calculation in correlation with the SXRD structure of PNU-21.

Synthesis of new chromeno-carbamodithioate derivatives and preliminary evaluation of their antioxidant activity and molecular docking studies.

New chromeno carbamodithioates (7a-i), have been synthesized from 2, 3-dimethyl-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (5), carbondisulphide and commercially available acyclic and cyclic secondary amines in acetonitrile with good to excellent yields. The free radical scavenging activity of novel chromone-carbamodithioate analogues was quantitatively estimated by spectrophotometric method. Whereas, molecular docking studies were performed with the active site of cyclooxygenase-2 to identify hydrogen bonding, hydrophobic and ionic interactions between protein and ligands. The compounds 7g and 7h demonstrated potent antioxidant activity with IC50 of 1.405±0.019mM and 1.382±0.35mM respectively compared to Ascorbic acid.