Molecular Docking of Some Quinazolinone Analogues as an EGFR Inhibitors

Background: Mutations that cause high expression of epidermal growth factor can lead to cancer. Therefore, this factor serves as a potential molecular target for cancer treatment, and inhibitors of this enzyme are of particular importance in the treatment of cancer. This study aimed to investigate the bioinformatics of inhibition of EGFR enzyme by a number of quinazolinone derivatives. Materials and Methods: This study was conducted based on a descriptive-analytical method. To investigate how quinazolinone derivatives bind to the active site of the enzyme, the chemical structure of the compounds was first plotted using ChemBioDrawUltra software (version 14). It was then transferred to Hyperchem software for energy optimization. Docking studies were performed using AutoDock software (version 4.2), and in the final stage, the results were analyzed using three programs, including AutoDockTools, DS Visualizer, and Ligplot. Results: Based on the results of docking studies, the most important bonds involved in drug-receptor binding are hydrophobic and hydrogen bonds. Among all the studied compounds, the best docking results are related to compound number 3. This compound with the most negative binding energy level (ΔGbind=-7.53 Kcal/mol) has a greater tendency to bind to key amino acids at the active site of the EGFR. Conclusion: In the end, due to the high effectiveness and docking results, it can be conclude that compound number 3 can be considered an effective erlotinib EGFR inhibitor.

Molecular Docking Evaluation of the Desert Truffles as Potent Antifungal Inhibitors

The research investigated the possible antifungal behavior of forty-four truffles bioactive compounds conducted to investigate the interaction modes of these inhibitors against three different types of the fungal proteins: Candida albicans, Blastomyces dermatitidis, and Ganoderma microsporum. The applied method in contrast to ketoconazole and griseofulvin revealed the possible anti-fungal agents ergosterol, Catechin gallate and rutin. With respect to Candida Albicans, the maximum possible binding energy was ergosterol (-11.75 Kcal/mol), followed then by catechin gallate (-11.46 Kcal/mol) then rutin (-9.90 Kcal/mol). Compared to Blastomyces, Ganoderma microsporum fungal protein with most negative binding energy among other components of the truffle is found to be of a relatively similar behavior for the same compounds. Ergosterol demonstrated the highest binding capacity for dermatitidis, while rutin scored the lowest against Ganoderma microsporum. The possible anti-fungal components of desert truffle have yet to be studied in vitro in the future.

Discovery of Sulforaphane as a Potent BACE1 Inhibitor Based on Kinetics and Computational Studies

BACE1 is the rate-limiting enzyme involved in the production and deposition of β-amyloid (Aβ). Since neurotoxic Aβ plays a critical role in Alzheimer’s disease (AD) pathogenesis, BACE1 has emerged as a key target for preventing AD. In the present study, the potential of sulforaphane, an isothiocyanate found in cruciferous vegetables, as a BACE1 inhibitor has been investigated. Sulforaphane exhibited six times more potent activity against BACE1 compared to well-known positive controls including resveratrol and quercetin. Sulforaphane presented selective and non-competitive BACE1 inhibitory activity with low off-target inhibition of BACE2 and other aspartic and serine proteases. In addition, sulforaphane presented negative binding energy, suggesting that the compound had a high affinity for BACE1. It interacted with locations other than the active binding sites of BACE1 through van der Waals forces. Overall, sulforaphane appeared to be a promising candidate with potent and selective BACE1 inhibitory properties that play an important role in AD prevention.

Drug-likeness of Phytic Acid and Its Analogues

Inositol hexakisphosphate is known to be the phosphorous reserve in plants particularly in the seeds. Though it has been known for its antinutrient properties for many years, recent research shed light to reveal it as a novel anticancer agent. Hence the present study investigates the drug-likeness of phytic acid and its analogues through bioinformatics methods. Two potential cancer drug targets such as mitogen activated kinase and inositol 1,4,5-triphosphate receptor are included in the study. Out of 50 selected analogues of phytic acid, 42 structures interact well with the chosen drug targets. The best interacting structures are 1-diphosinositol pentakisphosphate and 2,3,4,5,6-pentaphosphonooxycyclohexyl dihydrogen phosphate. For both of these structures, the negative binding energy obtained was -49.5 KJ/mol; this affirms the stability of the complex. ADME properties are also predicted to assess the drug-like properties of the compounds. The structure activity relationship model is generated for 12 compounds with experimental IC50 values.

Exploring the binding dynamics of BAR proteins

We used a continuum model based on the Helfrich free energy to investigate the binding dynamics of a lipid bilayer to a BAR domain surface of a crescent-like shape of positive (e.g. I-BAR shape) or negative (e.g. F-BAR shape) intrinsic curvature. According to structural data, it has been suggested that negatively charged membrane lipids are bound to positively charged amino acids at the binding interface of BAR proteins, contributing a negative binding energy to the system free energy. In addition, the cone-like shape of negatively charged lipids on the inner side of a cell membrane might contribute a positive intrinsic curvature, facilitating the initial bending towards the crescent-like shape of the BAR domain. In the present study, we hypothesize that in the limit of a rigid BAR domain shape, the negative binding energy and the coupling between the intrinsic curvature of negatively charged lipids and the membrane curvature drive the bending of the membrane. To estimate the binding energy, the electric potential at the charged surface of a BAR domain was calculated using the Langevin-Bikerman equation. Results of numerical simulations reveal that the binding energy is important for the initial instability (i.e. bending of a membrane), while the coupling between the intrinsic shapes of lipids and membrane curvature could be crucial for the curvature-dependent aggregation of negatively charged lipids near the surface of the BAR domain. In the discussion, we suggest novel experiments using patch clamp techniques to analyze the binding dynamics of BAR proteins, as well as the possible role of BAR proteins in the fusion pore stability of exovesicles.

Hydrogen-bonded assembly and binding affinity of the multi-point acceptor and isophthalic acid

Supermolecular complexes formed by oligophenyleneethynylene derivatives and isophthalic acid were studied using AM1 method to obtain binding energy. Electronic spectra and IR spectra of the complexes were calculated by INDO/CIS and AM1 methods based on AM1 geometries. Results indicated that the dimer could be formed by the monomers via hydrogen bonding because of the negative binding energy. Binding energy of the complexes was affected by electronegativity and steric effects of the substituents. The first UV absorptions and IR frequencies of N-H bonds of the complexes were both red-shifted compared with those of the monomers. The complexes could bind small molecules via hydrogen bonds, resulting in the change in UV absorptions and an increase in IR frequencies of N-H bonds.

Theoretical studies on the binding affinities of β-cyclodextrin to small molecules and monosaccharides

Equilibrium geometries and electronic structures of complexes between β-cyclodextrin (β-CD) and some small molecules as well as monosaccharides were investigated by Austin Model 1 (AM1) to obtain binding energy of the complexes. It was indicated that β-CD could bind the structurally similar solvent molecules and monosaccharides because of the negative binding energy of the complexes, and especially could show the chiral binding ability to monosaccharides with more hydroxyl groups, due to its chiral characteristics. The complexes were stabilized by the hydrogen bonding between β-CD and guests. Based on the AM1 optimized geometries, the IR spectra were calculated by AM1 method. Vibration frequencies of O-H bonds in the guests were red-shifted owing to the weakening of the O-H bonds with the formation of the complexes.

QUANTUM BOUND STATES FOR A DERIVATIVE NONLINEAR SCHRÖDINGER MODEL AND NUMBER THEORY

A derivative nonlinear Schrödinger model is shown to support localized N-body bound states for several ranges (called bands) of the coupling constant η. The ranges of η within each band can be completely determined using number theoretic concepts such as Farey sequences and continued fractions. For N≥3, the N-body bound states can have both positive and negative momenta. For η>0, bound states with positive momentum have positive binding energy, while states with negative momentum have negative binding energy.