Journal of Computational Biophysics and Chemistry

The understanding of the connections between Angiotensin peptides with the receptors in the Renin-angiotensin system (RAS) is not clear yet. The ACE2/Ang (1-7)/MAS axis, commonly referred to as the protective arm of the RAS, plays a crucial role in maintaining homeostasis within the cardiovascular system. Angiotensin 1-7 (Ang 1-7) is a heptapeptide an integral part of the protective arm of RAS and acts as a ligand binding to the MAS receptor. Understanding the signaling system of the ACE2/Ang (1-7)/MAS axis, which occupies an important place in the RAS, can be considered a serious putative target for the development of new cardiovascular and cancer drugs. It is very important to understand whether the Ang (1-7) ligand binds stably to MAS and, if so, how this affects the dynamics of the receptor. Therefore, we investigated how Ang (1-7) binding affects the stability and communication of the MAS receptor by utilizing molecular dynamics (MD) simulations and various computational techniques. Results indicated that Ang (1-7) was stably bonded to the MAS receptor over the 300ns simulation period. It was also observed that ligand binding caused a reduction in the fluctuations of the MAS residues. Major changes include a reduction in flexibility of the N-terminal domain, ICL1, ECL1, ECL2, ECL3, TM6 and C-terminal domain residues. Our findings presented in this study may provide a contribution to future studies seeking to gain a deeper understanding of the role of Ang (1-7) interaction with the MAS receptor in the RAS.

Curcumin can interact with a variety of molecules implicated in a wide range of disorders. It can also hinder dengue virus’s (DENV’s) ability to infect cells. This work used computational analysis to identify and forecast the most potent curcumin analogs against the DENV NS2B/NS3 protease. In this study, curcumin-like compounds were screened using a rational in-silico study, with the least similarity score, docking analysis, and then additional screening for suitable pharmacokinetic properties. According to the findings, DB11672 has been identified as the primary inhibitor of DENV NS2B/NS3 protease. It is recommended that additional research be done on this antiviral property of the lead compound as a part of the process of finding and developing a new drug against DENV.

Mycobacterium tuberculosis causes tuberculosis, an infectious disease. Pyrazinamide is a tuberculosis treatment. Metal–ligand–drug complexation can be used to improve the therapeutic efficacy of drugs. Copper pyrazinamide (CuPZA), a newly synthesized drug, is being considered for tuberculosis treatment. CuPZA was synthesized by soft synthetically reacting Cu (II) metal with pyrazinamide. The metal-drug complexes were characterized using elemental analysis, melting point determination, TGA analysis, FT-IR spectrometer, hot-stage microscopic study and X-ray crystallography. Copper (II) coordination with pyrazinamide was clearly demonstrated by the results of the characterization. For molecular modeling of the CuPZA novel compound, the density functional theory (DFT) method with B3LYP functional and 6-31G(d,$p)$ basis set was used. Chemical reactivity parameters such as the energy gap, global hardness and softness and the electrophilicity index demonstrate that the complex is chemically reactive in aqueous medium. Pharmacokinetic parameters studied revealed that the complex is a promising drug material, with good oral bioavailability and higher activity than first-line tuberculosis medications. The enzymes alanine aminotransferase (AST) and aspartate aminotransferase (ALT) were used to assess liver damage, whereas malondialdehyde (MDA), reduced glutathione (GSH), glutathione-S-transferase (GST) and superoxide dismutase (SOD) were used to assess liver antioxidant status. ALT, AST and GSH levels were not significantly different across all test parameters, but GST activity and MDA levels were significantly higher (p 0.05) in the 20mg CuPZA group compared to the control. CuPZA’s LD50 was lower (47.962g/ml) than PZA’s (83.624g/ml). According to the findings, pyrazinamide does not cause oxidative stress and is thus safer than CuPZA. CuPZA did not reduce antioxidant levels in rats, but it did cause oxidative stress. Furthermore, oxidative stress has no effect on liver enzyme levels, which are indicators of liver damage, indicating that the animals are in the early stages of oxidative stress. Copper pyrazinamide is a promising tuberculosis inhibitor with potential activity greater than first-line tuberculosis treatments. Copper pyrazinamide, on the other hand, should be used for tuberculosis treatment for a shorter period of time than pyrazinamide.

Hypoxia plays a critical role in melanoma development, but the characteristics of elemental oxygen in proteins and adaptation to hypoxia microenvironments are still unidentified. This study aims to explore oxygen contents (OCs) and differentially expressed proteins (DEP). Protein expression data were retrieved from Human Protein Atlas. The DEP in melanoma samples were compared with normal skin cells. We identified 1,969 DEP, and none of the genes coding these proteins were present on chromosome Y. The average oxygen content (AOC) was 7.24% higher in highly expressed proteins than lowly expressed proteins in melanoma and normal skin cells. The AOC is 2.36% higher in the up regulated proteins (URPs) in melanoma. The essential amino acids in the proteins in melanoma cells contributed to increased OC. Functional dissections of the high OCs in URP displayed that some of these proteins are associated with cytoskeleton, cyclins and cell cycle proteins. The URP interactions were generated using a STRING database. Majority of these URPs are associated in expression, exhibiting sufficient interactions with each other. This study provides useful information regarding protein expression in melanoma cells and the molecular mechanism of melanoma using stoichiogenomics.

In recent years, antimicrobial agents have been crucial in improving public health worldwide. However, due to improper usage, bacteria have developed resistance to these agents. This has led researchers to explore the use of heterocyclic compounds as alternative antimicrobial agents to combat resistance. Considering the success of heterocyclic derivatives in developing effective antimicrobial drugs, we conducted a 2D-QSAR (QSAR models using 2D-descriptors) study on novel pyrimidine derivatives and performed in silico simulations to evaluate their potential antibacterial activity against quinolone-resistant Escherichia coli. We used QSARINS V.2.2 (Insubria) software for the 2D-QSAR analysis and performed in silico absorption, distribution, metabolism, and excretion (ADME) and docking studies on 16 newly designed compounds. The best QSAR model had a high correlation coefficient ($R^2=0.9633$, $Q_{\mathrm{\text{LOO}}}^2=0.9538$, $Q_{\mathrm{\text{LMO}}}^2=0.9513$) and showed no outliers. Based on these favorable results, we designed 16 new compounds and predicted their antibacterial activity using the best equation. Amongst the top six designed compounds, which had the best docking scores were subjected to practical synthesis. Compound 3cd was found to be good candidature from in-vitro anti-E. Coli activity. This compound may be targeting the DNA gyrases and thus, have inhibitory activity against E. Coli. This observation was also supported by 100ns molecular dynamics and normal mode analysis results. The most promising compounds identified through these computational studies may be synthesized and tested as potential new drug candidates for treating bacterial infections.

All-atom molecular dynamics simulations have been performed on mixtures of tetrabutylammonium chloride-based deep eutectic solvent and two cosolvents — methanol and acetonitrile. Water, a highly polar protic solvent, strongly interacts with the DES components. Herein, we have chosen methanol, a protic solvent but less polar than water, and acetonitrile, an aprotic solvent, to investigate the structural modifications in DES and new interactions arising after the addition of cosolvent based on both polarity and the presence or absence of labile hydrogen. Of the two cosolvents, methanol is found to affect the interactions present in DES significantly. Strong hydrogen bond interaction occurs between the chloride anion and methanol, leading to changes in the behavior of the mixture at the microscopic level. The self-diffusivity of components of the DES increases with the addition of methanol and acetonitrile; however, the increase is relatively more significant in the latter due to fewer average numbers of H-bonds. The amplitudes of the peaks of the structure factor decrease with an increase in the cosolvent concentration, thereby confirming that cosolvent affects the long-range correlations.

Non-Fullerene acceptors (NFAs) are attracting much attention from scientists worldwide for their potential use in organic solar cells (OSC). Herein, we developed C-shaped NFAs acceptors (FA1–FA10) by performing end-capped alteration on GL1. The structural-property relation and optoelectronic characteristics were examined theoretically. Furthermore, the impact of structural changes on the optoelectronic characteristics of FA1–FA10 molecules was investigated by using density functional theory (DFT), and time-dependent DFT. The photo-physical and optoelectronic features such as frontier molecular orbitals, electron–hole overlapping, excitation and binding energy, molecular electrostatic potential, the density of states, transition density matrix, open circuit voltage, and reorganization energies of hole and electron, of the designed materials have been simulated. Compared to GL1 (R), the developed materials displayed a red-shifted absorption (ranges 769.84–856.36nm), better electric-charge movement, lower binding (0.30eV), and excitation energies (1.28eV), and narrower bandgaps (ranges 1.59–1.79eV), respectively. Therefore, we suggest these to synthetic researchers for the future development of efficient OSCs.

The cortical excitability rate correlates with epileptic seizures, which should be modulated in a finite time to prevent brain damage. Deep brain stimulation (DBS) is a successful treatment for patients with refractory epilepsy. This study proposes a closed-loop DBS control method that uses a Fixed-Time Integral Super-Twisting Sliding Mode Controller (FTISTSMC) to stop simulated epileptiform discharges within a limited time by modifying cortical excitability in the human Cortical Model (CM). First, the simulated stimulus current in the DBS method is injected into the state variable of the excitatory neurons population in CM. Then, the FTISTSMC is applied to the state variable described above to regulate the stimulus current value during the stimulation process to reduce the possible destructive effects of electrical pulses on the behavior of the healthy neurons. The proposed controller has some characteristics causing the simulated epileptic activity to become normal and the tracking error of the healthy state to be completely zero after 4.7s. In addition, it is possible to resolve the chattering and singularity problems and completely control epileptic seizures within a fixed and finite time frame.