Cancer remains to be among the major health issues in the global context, and safe and more efficient treatment is sought to be identified. EGFR, or Epidermal Growth Factor Receptor, is a promising target of one of the strategies aimed at the survival and growth of cancer cells. We have investigated, in this study, a set of more recently designed 2-(piperazin -1-yl)- 1H -benzo[d]imidazole derivatives through computer-based methods to determine their potential as EGFR inhibitors. The stability of the most promising complex was tested by the molecular dynamics simulation after molecular docking was used to predict the binding affinity of these compounds to EGFR. Other drug-like characteristics that were also looked at include absorption, bioavailability, and chemical suitability. Out of the tested compounds, one of them specifically the compound marked as A4 was interesting as it demonstrated high binding affinity, desirable pharmacokinetic properties, and a stable interaction with EGFR. The above findings indicate that compound A4 is a promising anti-cancer drug to be developed further. To establish its potential, additional laboratory tests are suggested.

The mechanism of excited state proton transfer between guanine and cytosine in the Watson-Crick base pair was studied with experimental and theoretical methods. When irradiated with UV light the water solution of the equimolecular mixture of guanine and cytosine indicates a photoreaction with a rate constant 48.07×10-4 min-1. The backward dark reaction occurs with a rate constant 12.03×10-4 min-1. One of the identified processes is an excited-state proton transfer (ESPT). The mechanism of the photoreaction was followed at the B3LYP/aug-cc-pVDZ level of theory in water surroundings (according to PCM). We tested two mechanisms: intrinsic reaction coordinate (IRC) and Linear interpolation of internal coordinates (LIIC) between a base pair and a conical intersection S0/S1. They both showed that the ESPT occurs along 1pp* excited-state reaction paths.

In this study, 15 vanillin-derived compounds were downloaded from the ZINC15 database in mol2 format. A molecular docking study was performed using the Igemdock program with PDB ID: 6QXG protein using the Igemdock program. As a result of these processes, the five lowest energy compounds were identified. Accordingly, the best binding molecules are 13, 12, 14, 3 and 10, respectively. Molecular docking was performed with five selected molecules, and Autodock Vina embedded Chimera 1.17.3 programs. The interactions of the molecules with the protein were analysed. ADME studies were also performed. According to the in silico results, this molecule seems promising in terms of its potential to be turned into a drug in the future. However, more detailed in vivo and in vitro studies with these molecules are needed. As a result of these processes, some quantum chemical properties of the lowest energy molecule were analysed with the help of the Entos-Envision web server.

A theoretical DFT investigation of the reaction of 3,4-dihydro-2H-pyrrole-1-oxide (nitrone) with two alkenes cis- and trans-2-butene has been thoroughly probed at B3LYP/6-31G(d) level of theory. The regioselectivity as well as the detailed mechanism of reaction has been studied and analyzed. The reaction is characterized by a concerted asynchronous mechanism and the products P2 and P4 are the most favorable products kinetically and thermodynamically. A good agreement with the experimental data has been found.

Uric acid (UA) is a biological molecule which is susceptible to be investigated theoretically. A theoretical investigation is carried out in the gas phase and by water effect at the ground state by using density functional theory method (DFT) at the B3LYP/6-31(d) and B3LYP/ LANL2DZ levels on the structure of different chemical forms of Uric Acid (UA) and its metal complexes. Solvent effect (water) is included using the polarizable continuum model (PCM). Neutral structures (ketonic, enolic, dimeric, monohydrate) and anionic structures has been fully optimized. Furthermore, and in order to estimate the Brönsted acidity of (UA), the interaction of both enolic and ketonic forms with alkali meta cations (Li+, Na+, K+, Be++, Mg++, Ca++) was calculated in M(UA)+n complex structures. Proton acidity of (UA) and its complexes was estimated by calculating deprotonation energy (DE) and δ (ppm)11H NMR chemical shift using GIAO method. Metal cations effects on distinct N-H and O-H stretching vibrational modes of studied structures have also been examined. Further, we explored the geometry, and acidity of several uric acid transition metal complexes M(UA)2+n (M= Zn+2, Cd+2, Ag+, Cu+) in water. The complex was calculated using mixed basis set 6-31G(d) and LANL2DZ (on the transition metal).

Exploring the medicinal significance of bioactive compounds through computational methods is an increasingly practiced approach in contemporary medicinal research. This study aims to assess the antidiabetic potential of compounds extracted from the plant Nyctanthes arbor tristis by evaluating their ability to inhibit the carbohydrate metabolic enzyme α-glucosidase. The research work was conducted through molecular docking calculation, molecular dynamics simulation (MDS), and ADMET prediction techniques. Among the compounds, arbortistoside-C (NAS03), and arbortristoside-D (NAS04) found in the seed of the plant were identified as hit inhibitors of the target protein with docking scores, -9.9 and -9.4 kcal/mol, respectively. The compounds showed a comparable docking score with the drug of diabetes acarbose (-8.6 kcal/mol). Geometrical parameters like radius of gyration, solvent accessibility surface, root mean square deviation, and root mean square fluctuation from MDS supported the stability of the protein-ligand complex. MMPBSA calculations demonstrated the stability and feasibility of the complex with binding free energy changes of -29.06±6.06 and -23.58±8.80 kcal/mol for compounds NAS03 and NAS04, respectively. The ADMET prediction suggested the drug-likeness of the compounds compared with that of the standard drugs. The results could be used in proposing the antidiabetic potential of the two compounds from the plant as a potential inhibitors of α-glucosidase enzyme. Further, in vitro and in vivo experiments on such compounds could be a more reliable path to validate the output of this computational research.

The discovery of the importance of angiogenesis in the mechanisms of tumor growth has empowered the improvement of new particles that are utilized in the therapy of various cancers. The goal of this research was to identify novel compounds functioning as potent VEGFR2 inhibitors in silico. It is an interesting therapeutic target for developing new anti-angiogenic drugs. In this work, molecular simulation studies of enzyme inhibition was carried out by structure-based virtual screening with FlexX program of VEGFR2. This approach makes it possible to model the interactions between a protein and thousands of small chemical compounds. A collection of 6,000 compounds originating from the ZINC chemical library, were tested against the active site of VEGFR2. The ADME-Tox characteristics and molecular dynamics simulation of the potential compounds were also examined. At the end of this screening, the compounds ZINC01534124 and ZINC00588595 appear as new inhibitors theoretically more active towards VEGFR2. Again, these inhibitors have shown significant binding energy by interacting with important residues in the active site. Furthermore, the in silico prediction of a similar drug positively informs us about the ADME-Tox properties of these new compounds. Finally, the stable binding of VEGFR2 with ZINC01534124 and ZINC00588595 is shown using 100 ns molecular dynamics simulations. These findings point to the chemicals ZINC01534124 and ZINC00588595 as potential candidates for VEGFR2 inhibitor research. They might also act as a starting point for further chemical modifications in order to produce therapeutically relevant anti-angiogenic medications.

Tranglutaminase-2 (Tgase2) is one of the primary Transglutaminase enzyme family members having a significant role in Ca2+ -dependent and -independent post-translational modifications. It has been previously reported that Tgase2 has significant regulatory roles over metabolic functions such as signaling pathways, inflammatory response, and wound healing. In particular, many cancer types’ prognosis includes over Tgase2 activity since it might induce metastasis through regulating crosslinking of extracellular matrix (ECM) proteins, and tumor proliferation via leading spheroid formation. Considering these fundamentals, discovery of novel chemical compounds to inhibit Tgase2 activity might be a strong approach in cancer treatment. Furthermore, it’s known that Tgase2 activity might be inhibited through blocking its allosteric site with chemical compounds. As such, a drug library including 12,111 small compounds were virtually screened to allosteric site of Tgase2. The study has been validated by repetition the strategy with previously discovered inhibitors. Allosteric and active sites of Tgase2 have been demonstrated with protein-protein docking technique. Eventually, recently discovered ligands have been characterized according to their ADME and toxicity profiles. Results have demonstrated that Eltrombopag, Talniflumate, and Lumacaftor drugs might be repurposed in the inhibition of Tgase2 since that they exhibit high binding affinity, ADME, and toxicity properties comparing the known inhibitors.

ABSTRACT To evaluate the possible actions of five novels' fluoxetine prodrug derivatives, a number of them have been suggested. The prodrug method aims to increase the number of biopharmaceutical drug deliveries and the drug's pharmacokinetics and/or bioavailability. This strategy has additional benefits, such as therapeutic targeting by enzyme-triggered drug release. The extent of butyrylcholine esterase-mediated activation can be predicted using computational models, which also aid in the development of prodrugs. A variety of computational techniques, such as molecular docking and molecular dynamics simulations, which determined the binding affinities of the five fluoxetine prodrug derivatives molecules to the enzyme binding site by docking them. Computer simulations were performed with GOLD program (CCDC) version 5.43, and the compounds were created with ChemDraw version 22.2 (professional version). They were then evaluated for selectivity with BChE, and a control for comparison was butyrylthiocholine. and for 1nanosecond, SiBioLead server was used to run molecular dynamic simulations of compound A1 complexes with BChE enzyme. RMSD, RMSF, RG results, SASA result, and enzyme energy were estimated during this time. Results showed that the prodrug was activated by BChEenzyme, demonstrating the highest binding energy inside the active cite of the enzyme. PLP fitness values of 86.65, 80,81, and 82.819 were recorded by compounds A1, A2, and A4. This study reveals that fluoxetine prodrug molecular design guided by computational simulations can be more mechanistic and less empirical. Moving forward, the earliest possible stage in the development process should be when prodrugs' action is predicted by molecular modeling tools.

Receptor tyrosine kinases (RTK) are considered one of the main targets in cancer therapy due to their high expression. Unfortunately, multiple molecular mechanisms of resistance have been identified, leading to drug resistance and toxicity, which increases the need to discover new structural tyrosine kinase inhibitors. Instead of the rigid molecular docking method, molecular dynamic simulations can treat both the ligand and the protein in a flexible way. This lets the receptor-binding site fit around the new ligand. Also, the effect of explicit water molecules can be studied directly, and very accurate binding free energies can be obtained. The cytotoxic study does not explain the mechanism by which the tested compound could act, so further costly biological studies are needed. So, molecular dynamics is used as a computational technique that simulates the dynamic behavior of molecular systems as a function of time. Using Maestro v 13.0.135 interface (Schrodinger, New York, NY, 2021), molecular dynamic simulation was done with two proteins (EGFR and HER2) that are co-crystallized with the same ligand of a dual EGFR/HER2 inhibitor (TAK-285), and then they were tested with compounds of highly cytotoxic activity (2g and 4g) of suspected dual TKI activity from a previous study. According to the resulted data that were shown in the simulation interactions diagram reports, we recognize that the 2g compound showed a good interaction complex with both 3POZ (EGFR) and 3RCD (HRE2) proteins, while only the 4 g-3RCD complex showed a good interaction report. So, 2g could be considered a dual EGFR/HER2 inhibitor and 4g as an HER2 inhibitor, and for further investigation, both compounds could be tested further with other biological studies, especially enzyme inhibitory assays with suspected promising results.