MOLECULAR DOCKING STUDIES OF BERBERINE DERIVATIVE AS NOVEL MULTITARGET PCSK9 AND HMGCR INHIBITORS

Hypercholesterolemia is a high risk for cardiovascular diseases, stroke, and mortality. Multitarget directed ligands (MTDLs) with dual inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) are the potential targets for the treatment of hyperlipidemia. In this work, a novel series of Berberine (BBR) derivatives was designed based on molecular docking to serve as MTDLs for PCSK9 and HMGCR. The binding energy of BBR derivatives was investigated, which confirmed that all the designed compounds showed better binding energy than the parent BBR for both enzymes. The effect of different benzenesulfonyl ring substituents was explored to improve the binding affinity. The obtained results indicated that there are significant differences in their interactions and mode of binding. All 24 designed compounds were identified as the potent multitarget inhibitors because the increase of hydrogen bond, hydrophobic and electrostatic interactions were observed. Among them, 12 could be selected as the best candidate for further study as potential multitarget PCSK9 and HMGCR inhibitors for anti-hypercholesterolemia. The obtained result suggested that the introduction of the nitro- group plays a vital role in the binding pose of the BBR derivative. Finally, in silico study confirmed that most of the compounds pass the drug likeliness properties

Molecular Design of the Triphenylamine Substitution on Isoindigo-Based as Promising Hole Transport Materials for Perovskite Solar Cell

The performance of perovskite solar cells (PSCs) controlling the hole mobility is the fundamental importance. The development of novel hole transport materials (HTMs) with good stability, low cost and high hole mobility for PSCs has attracted much attention for researchers. In this work, new isoindigo-based HTMs substituted with two triphenylamine (TPA) with the donor-acceptor-donor (D-A-D) architecture, were designed computationally. The effect of π-extension influence on the charge transfer process was investigated by insertingof two vinyl groups between acceptor and donor parts (D-π-A-π-D). The correlation between electronic structure and hole transport properties of the designed HTMs was determined by tuning the connection between donor and acceptor. The ground state of the HTMs was fully optimized by DFT method at B3LYP/6-31G(d,p), and the excited state, absorption and emission properties of the  HTMs were carried out by using the TD-DFT at cam-B3LYP/6-31G(d,p) in dichloromethane solvent based on the conductor-like polarizable continuum model (C-PCM). The calculated HOMO, LUMO and band gap values of the HTMs showed higher values than that of MAPbI3 (perovskite). Hence, the charge distribution in HOMO and LUMO of our designed structures could qualitatively predicted the carrier injection and transportation in the PSCs. The adsorption spectra were broader, indicating that the proposed HTMs absorbed a large amount of visible light, which might impact the electron delocalization. This designed HTMs would have the potential for synthesis of new HTMs

A DFT-based Analysis of Metals Adsorption on Chitosan Monomer

The generation of waste electrical and electronic equipment (WEEE or E-waste) has been noted as an increasing category of waste. In this work, the density functional theory (DFT) was used to investigate the adsorption process between chitosan (CS) and metals at the B3LYP level with 6-31G(d,p) and LANL2DZ basis sets. The effect of solvent was included using the polarizable continuum model (PCM) consisting of water. Ag+, As3+, Ba2+, Be2+, Cd2+, Co2+, Cr3+, Cu2+, Hg2+, Li+, Mn2+, Ni2+, Pb2+, Pd2+, Sb3+, Sn2+, Sr2+, Tl+, and Zn2+ have been selected to be studied because of high impact in E-waste. Different analyses were carried out: adsorption energy, HOMO-LUMO energy gaps, hardness, softness, frontier molecular orbitals, and molecular electrostatic potential (MEP), and all of which are necessary to predict the formation of complexes. The interaction between CS and metal species was shown in almost all cases as covalent partial. In addition, all metals were placed closeer to the nitrogen atom than the oxygen atom of CS because the charge density of the nitrogen is increased in the formation of the Schiff base. Finally, the monomer derived from CS has good stability in water and is, therefore, considered as a good material in the field of environmental pollution

Molecular Docking and NMR Binding Studies to Identify Novel Inhibitors of Human Phosphomevalonate Kinase

Phosphomevalonate kinase (PMK) phosphorylates mevalonate-5-phosphate (M5P) in the mevalonate pathway, which is the sole source of isoprenoids and steroids in humans. We have identified new PMK inhibitors with virtual screening, using autodock. Promising hits were verified and their affinity measured using NMR-based 1H–15N heteronuclear single quantum coherence (HSQC) chemical shift perturbation and fluorescence titrations. Chemical shift changes were monitored, plotted, and fitted to obtain dissociation constants (Kd). Tight binding compounds with Kd’s ranging from 6–60 μM were identified. These compounds tended to have significant polarity and negative charge, similar to the natural substrates (M5P and ATP). HSQC cross peak changes suggest that binding induces a global conformational change, such as domain closure. Compounds identified in this study serve as chemical genetic probes of human PMK, to explore pharmacology of the mevalonate pathway, as well as starting points for further drug development