Favorable Free Energy Research Articles

Engineering Single-Atom Electrocatalysts for Enhancing Kinetics of Acidic Volmer Reaction.

The design of active and low-cost electrocatalyst for hydrogen evolution reaction (HER) is the key to achieving a clean hydrogen energy infrastructure. The most successful design principle of hydrogen electrocatalyst is the activity volcano plot, which is based on Sabatier principle and has been used to understand the exceptional activity of noble metal and design of metal alloy catalysts. However, this application of volcano plot in designing single-atom electrocatalysts (SAEs) on nitrogen doped graphene (TM/N4C catalysts) for HER has been less successful due to the nonmetallic nature of the single metal atom site. Herein, by performing ab initio molecular dynamics simulations and free energy calculations on a series of SAEs systems (TM/N4C with TM = 3d, 4d, or 5d metals), we find that the strong charge-dipole interaction between the negatively charged *H intermediate and the interfacial H2O molecules could alter the transition path of the acidic Volmer reaction and dramatically raise its kinetic barrier, despite its favorable adsorption free energy. Such kinetic hindrance is also experimentally confirmed by electrochemical measurements. By combining the hydrogen adsorption free energy and the physics of competing interfacial interactions, we propose a unifying design principle for engineering the SAEs used for hydrogen energy conversion, which incorporates both thermodynamic and kinetic considerations and allows going beyond the activity volcano model.

Comparison of Receptor-Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations.

Alchemical absolute binding free energy calculations are of increasing interest in drug discovery. These calculations require restraints between the receptor and ligand to restrict their relative positions and, optionally, orientations. Boresch restraints are commonly used, but they must be carefully selected in order to sufficiently restrain the ligand and to avoid inherent instabilities. Applying multiple distance restraints between anchor points in the receptor and ligand provides an alternative framework without inherent instabilities which may provide convergence benefits by more strongly restricting the relative movements of the receptor and ligand. However, there is no simple method to calculate the free energy of releasing these restraints due to the coupling of the internal and external degrees of freedom of the receptor and ligand. Here, a method to rigorously calculate free energies of binding with multiple distance restraints by imposing intramolecular restraints on the anchor points is proposed. Absolute binding free energies for the human macrophage migration inhibitory factor/MIF180, system obtained using a variety of Boresch restraints and rigorous and nonrigorous implementations of multiple distance restraints are compared. It is shown that several multiple distance restraint schemes produce estimates in good agreement with Boresch restraints. In contrast, calculations without orientational restraints produce erroneously favorable free energies of binding by up to approximately 4 kcal mol-1. These approaches offer new options for the deployment of alchemical absolute binding free energy calculations.

A model for cis-regulation of transcriptional condensates and gene expression by proximal lncRNAs

Long noncoding RNAs (lncRNAs) perform several important functions in cells including cis-regulation of transcription. Barring a few specific cases, the mechanisms underlying transcriptional regulation by lncRNAs remain poorly understood. Transcriptional proteins can form condensates via phase separation at protein-binding loci (BL) on the genome (e.g., enhancers and promoters). lncRNA-coding genes are present at loci in close genomic proximity of these BL and these RNAs can interact with transcriptional proteins via attractive heterotypic interactions mediated by their net charge. Motivated by these observations, we propose that lncRNAs can dynamically regulate transcription in cis via charge-based heterotypic interactions with transcriptional proteins in condensates. To study the consequences of this mechanism, we developed and studied a dynamical phase-field model. We find that proximal lncRNAs can promote condensate formation at the BL. Vicinally localized lncRNA can migrate to the BL to attract more protein because of favorable interaction free energies. However, increasing the distance beyond a threshold leads to a sharp decrease in protein recruitment to the BL. This finding could potentially explain why genomic distances between lncRNA-coding genes and protein-coding genes are conserved across metazoans. Finally, our model predicts that lncRNA transcription can fine-tune transcription from neighboring condensate-controlled genes, repressing transcription from highly expressed genes and enhancing transcription of genes expressed at a low level. This nonequilibrium effect can reconcile conflicting reports that lncRNAs can enhance or repress transcription from proximal genes.

Design and development of novel potential inhibitors of the human USP21 enzyme using a pharmacophore-based virtual screening technique.

An overexpression and increase have been observed in the concentration and activity of the USP21 enzyme in many cancers, necessitating the need for the development of new inhibitor drugs against the same. The current study attempts to discover one such novel potential inhibitor of USP21 by the application of various bioinformatics techniques which include molecular modelling, pharmacophore mapping, and pharmacophore-based virtual screening, molecular docking, and ADMET prediction followed by molecular dynamics simulations. Following this inverted-funnel-like approach, we finally ended up with one ligand- ZINC02422616 which displays a very high binding affinity towards the USP21 domain. This ligand contains all the pharmacophoric features displayed by the compounds that are potential inhibitors of the USP21 domain. Moreover, it shows a favourable pharmacokinetic, pharmacodynamic, and ADMET profile along with strong hydrophobic interaction and hydrogen bonding with the domain. Simulation studies showed that the complex remains stable over time, with the bound protein displaying a more constrained motion in the conformational space compared to the unbound form. The ligand showed a highly favourable free energy landscape/surface, forming several energy minimas in contrast to the unbound domain in which most conformations occupied a relatively higher energy state. Moreover, the ligand also displayed a Kd of 422.8nM and a free energy of binding ΔG of -8.6kcal/mol, both of which indicate a very high affinity towards the target domain.This potential drug candidate can then be used as a viable treatment method for many types of cancers caused by USP21. his article is protected by copyright. All rights reserved.

N-Doping Coupled with Co-Vacancies Activating Sulfur Atoms and Narrowing Bandgap for CoS Toward Synergistically Accelerating Hydrogen Evolution.

The combination of hetero-elemental doping and vacancy engineering will be developed as one of the most efficient strategies to design excellent electrocatalysts for hydrogen evolution reaction (HER). Herein, a novel strategy for N-doping coupled with Co-vacancies is demonstrated to precisely activate inert S atoms adjacent to Co-vacancies and significantly improve charge transfer for CoS toward accelerating HER. In this strategy, N-doping favors the presence of Co-vacancies, due to greatly decreasing their formation energy. The as-developed strategy realizes the upshift of S 3p orbitals followed by more overlapping between S 3py and H 1s orbitals, which results in the favorable hydrogen atom adsorption free energy change (ΔGH ) to activate inert S atoms as newborn catalytical sites. Besides, this strategy synergistically decreases the bandgap of CoS, thereby achieving satisfactory electrical conductivity and low charge-transfer resistance for the as-obtained electrocatalysts. With an excellent HER activity of -89.0mV at 10.0mA cm-2 in alkaline environments, this work provides a new approach to unlocking inert sites and significantly improving charge transfer toward cobalt-based materials for highly efficient HER.

In Silico Analysis of a GH3 β-Glucosidase from Microcystis aeruginosa CACIAM 03.

Cyanobacteria are rich sources of secondary metabolites and have the potential to be excellent industrial enzyme producers. β-glucosidases are extensively employed in processing biomass degradation as they mediate the most crucial step of bioconversion of cellobiose (CBI), hence controlling the efficiency and global rate of biomass hydrolysis. However, the production and availability of these enzymes derived from cyanobacteria remains limited. In this study, we evaluated the β-glucosidase from Microcystis aeruginosa CACIAM 03 (MaBgl3) and its potential for bioconversion of cellulosic biomass by analyzing primary/secondary structures, predicting physicochemical properties, homology modeling, molecular docking, and simulations of molecular dynamics (MD). The results showed that MaBgl3 derives from an N-terminal domain folded as a distorted β-barrel, which contains the conserved His-Asp catalytic dyad often found in glycosylases of the GH3 family. The molecular docking results showed relevant interactions with Asp81, Ala271 and Arg444 residues that contribute to the binding process during MD simulation. Moreover, the MD simulation of the MaBgl3 was stable, shown by analyzing the root mean square deviation (RMSD) values and observing favorable binding free energy in both complexes. In addition, experimental data suggest that MaBgl3 could be a potential enzyme for cellobiose-hydrolyzing degradation.

In search of Pca21 phase ferroelectrics

In recent years, hafnia-based ferroelectrics have attracted enormous attention due to their capability of maintaining ferroelectricity below 10 nm thickness and excellent compatibility with microelectronics flow lines. However, the physical origin of their ferroelectricity is still not fully clear, although it is commonly attributed to a polar Pca21 orthorhombic phase. The high-temperature paraelectric phases (the tetragonal phase or the cubic phase) do not possess a soft mode at the Brillouin zone center, thus the ferroelectric distortion has to be explained in terms of trilinear coupling among three phonon modes in the tetragonal phase. It is necessary to explore new materials with possible ferroelectricity due to the polar Pca21 phase, which in turn should be very helpful in evaluating the microscopic theory for ferroelectric hafnia. In this work, based on the idea of the Materials Genome Engineering, a series of hafnia-like ferroelectrics have been found, exemplified by LaSeCl, LaSeBr, LuOF and YOF, which possess adequate spontaneous polarization values and also relatively favorable free energies for the polar phase. Their common features and individual differences are discussed in detail. In particular, a promising potential ferroelectric material, Pca21 phase LuOF, is predicted and recommended for further experimental synthesis and investigation.

Structural and molecular insights into tacrine-benzofuran hybrid induced inhibition of amyloid-β peptide aggregation and BACE1 activity

Amyloid-β (Aβ) aggregation and β-amyloid precursor protein cleaving enzyme 1 (BACE1) are the potential therapeutic drug targets for Alzheimer’s disease (AD). A recent study highlighted that tacrine-benzofuran hybrid C1 displayed anti-aggregation activity against Aβ42 peptide and inhibit BACE1 activity. However, the inhibition mechanism of C1 against Aβ42 aggregation and BACE1 activity remains unclear. Thus, molecular dynamics (MD) simulations of Aβ42 monomer and BACE1 with and without C1 were performed to inspect the inhibitory mechanism of C1 against Aβ42 aggregation and BACE1 activity. In addition, a ligand-based virtual screening followed by MD simulations was employed to explore potent new small-molecule dual inhibitors of Aβ42 aggregation and BACE1 activity. MD simulations highlighted that C1 promotes the non aggregating helical conformation in Aβ42 and destabilizes D23–K28 salt bridge that plays a vital role in the self-aggregation of Aβ42. C1 displays a favourable binding free energy (–50.7 ± 7.3 kcal/mol) with Aβ42 monomer and preferentially binds to the central hydrophobic core (CHC) residues. MD simulations highlighted that C1 strongly interacted with the BACE1 active site (Asp32 and Asp228) and active pockets. The scrutiny of interatomic distances among key residues of BACE1 highlighted the close flap (non-active) position in BACE1 on the incorporation of C1. The MD simulations explain the observed high inhibitory activity of C1 against Aβ aggregation and BACE1 in the in vitro studies. The ligand-based virtual screening followed by MD simulations identified CHEMBL2019027 (C2) as a promising dual inhibitor of Aβ42 aggregation and BACE1 activity. Communicated by Ramaswamy H. Sarma

Microscopic Understanding of the Conformational Stability of the Aggregated Nonamyloid β Components of α-Synuclein.

Self-association of α-synuclein peptides into oligomeric species and ordered amyloid fibrils is associated with Parkinson's disease, a progressive neurodegenerative disorder. In particular, the peptide domain formed between the residues Glu-61 (or E61) and Val-95 (or V95) of α-synuclein, typically termed the "nonamyloid β component" (NAC), is known to play critical roles in forming aggregated structures. In this work, we have employed molecular dynamics simulations to explore the conformational properties and relative stabilities of aggregated protofilaments of different orders, namely, tetramer (P(4)), hexamer (P(6)), octamer (P(8)), decamer (P(10)), dodecamer (P(12)), and tetradecamer (P(14)), formed by the NAC domains of α-synuclein. Besides, center-of-mass pulling and umbrella sampling simulation methods have also been employed to characterize the mechanistic pathway of peptide association/dissociation and the corresponding free energy profiles. Structural analysis showed that the disordered C-terminal loop and the central core regions of the peptide units lead to more flexible and distorted structures of the lower order protofilaments (P(4) and P(6)) as compared to the higher order ones. Interestingly, our calculation shows the presence of multiple distinctly populated conformational states for the lower order protofilament P(4), which may drive the oligomerization process along multiple pathways to form different polymorphic α-synuclein fibrillar structures. It is further observed that the nonpolar interaction between the peptides and the corresponding nonpolar solvation free energy play a dominant role in stabilizing the aggregated protofilaments. Importantly, our result showed that reduced cooperativity during the binding of a peptide unit beyond a critical size of the protofilament (P(12)) leads to less favorable binding free energy of a peptide.

Potential of Onchocerca ochengi inosine-5′-monophosphate dehydrogenase (IMPDH) and guanosine-5′-monophosphate oxidoreductase (GMPR) as druggable and vaccine candidates: immunoinformatics screening

Onchocerciasis is a vector-borne disease caused by the filarial nematode Onchocerca volvulus, which is responsible for most of the visual impairments recorded in Africa, Asia and the Americas. It is known that O. volvulus has similar molecular and biological characteristics as Onchocerca ochengi in cattle. This study was designed to screen for immunogenic epitopes and binding pockets of O. ochengi IMPDH and GMPR ligands using immunoinformatic approaches. In this study, a total of 23 B cell epitopes for IMPDH and 7 B cell epitopes for GMPR were predicted using ABCpred tool, Bepipred 2.0 and Kolaskar and Tongaonkar methods. The CD4+ Th computational results showed 16 antigenic epitopes from IMPDH with strong binding affinity for DRB1_0301, DRB3_0101, DRB1_0103 and DRB1_1501 MHC II alleles while 8 antigenic epitopes from GMPR were predicted to bind DRB1_0101 and DRB1_0401 MHC II alleles, respectively. For the CD8+ CTLs analysis, 8 antigenic epitopes from IMPDH showed strong binding affinity to human leukocyte antigen HLA-A*26:01, HLA-A*03:01, HLA-A*24:02 and HLA-A*01:01 MHC I alleles while 2 antigenic epitopes from GMPR showed strong binding affinity to HLA-A*01:01 allele, respectively. The immunogenic B cell and T cell epitopes were further evaluated for antigenicity, non-alllergernicity, toxicity, IFN-gamma, IL4 and IL10. The docking score revealed favorable binding free energy with IMP and MYD scoring the highest binding affinity at −6.6 kcal/mol with IMPDH and −8.3 kcal/mol with GMPR. This study provides valuable insight on IMPDH and GMPR as potential drug targets and for the development of multiple epitope vaccine candidates. Communicated by Ramaswamy H. Sarma

A comparative study on inclusion complex formation between formononetin and β-cyclodextrin derivatives through multiscale classical and umbrella sampling simulations

Formononetin, a naturally occurring isoflavone exhibits a wide range of therapeutic applications including antioxidant, anti-tumor, antiviral, anti-diabetic and neuroprotective activities. However, the low hydro-solubility of formononetin has limited its prospective use in cosmetic, neutraceutical and pharmaceutical industries. Cyclodextrins (CDs), especially β-CD and its derivatives have emerged as promising agents to improve the water solubility of poorly hydrosoluble compounds by the formation of inclusion complexes. We employed multiscale (1000 ns) explicit solvent and umbrella sampling molecular dynamics (MD) simulations to study the interactions and thermodynamic parameters of inclusion complex formation between formononetin and five most commonly used β-CD derivatives. Classical MD simulations revealed two possible binding conformations of formononetin inside the central cavity of hydroxypropyl-β-CD (HP-β-CD), randomly methylated-β-CD (ME-β-CD), and sulfobutylether-β-CD (SBE-β-CD). The binding conformation with the benzopyrone ring of formononetin inside the central cavity of β-CD derivatives was more frequent than the phenyl group occupying the hydrophobic cavity. These interactions were supported by a variety of non-bonded contacts including hydrogen bonds, pi-lone pair, pi-sigma, and pi-alkyl interactions. Formononetin showed favorable end-state MD-driven thermodynamic binding free energies with all the selected β-CD derivatives, except succinyl-β-CD (S-β-CD). Furthermore, umbrella sampling simulations were used to investigate the interactions and thermodynamic parameters of the host-guest inclusion complexes. The SBE-β-CD/formononetin inclusion complex showed the lowest binding energy signifying the highest affinity among all the selected host-guest inclusion complexes. Our study could be used as a standard for analyzing and comparing the ability of different β-CD derivatives to enhance the hydro-solubility of poorly soluble molecules.

Singlet-oxygen-driven photocatalytic degradation of gaseous formaldehyde and its mechanistic study

Conventional studies on photocatalytic oxidation reaction have focused primarily on hydroxyl radical (•OH) as a major reactive oxygen species (ROS). This perspective may not be suitable for gaseous HCHO photodegradation due to the short lifetime and diffusion length of •OH. Identification of divergent ROS and understanding their characteristics for the gas-phase photocatalytic oxidation are further required. Here, we report a BiOI/TiO2 p-n junction photocatalyst, which uses mobile singlet oxygen (1O2) as the main ROS for gaseous HCHO photooxidation. The introduction of p-n heterojunctions causes a charge transfer that prefers mobile 1O2 generation rather than •OH due to an energetically favorable desorption free energy, accelerating HCHO oxidation. Finally, we demonstrated the photocatalytic filter performance of HCHO-to-CO2 conversion for 150 h with a conversion efficiency of 87 ± 1.3 % in a single-pass reactor. Our systematic study reveals the potential of the overlooked 1O2-driven gaseous HCHO photocatalytic degradation process.

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies.

Breast cancer (BC) is one of the main types of cancer that endangers women's lives. The characteristics of triple-negative breast cancer (TNBC) include a high rate of recurrence and the capacity for metastasis; therefore, new therapies are urgently needed to combat TNBC. Dual targeting HDAC6 and Hsp90 has shown good synergistic effects in treating metastatic TNBC. The goal of this study was to find potential HDAC6 and Hsp90 dual inhibitors. Therefore, several in silico approaches have been used. An e-pharmacophore model generation based on the HDAC6-ligand complex and subsequently a pharmacophore-based virtual screening on 270,450 natural compounds from the ZINC were performed, which resulted in 12,663 compounds that corresponded to the obtained pharmacophoric hypothesis. These compounds were docked into HDAC6 and Hsp90. This resulted in the identification of three compounds with good docking scores and favorable free binding energy against the two targets. The top three compounds, namely ZINC000096116556, ZINC000020761262, and ZINC000217668954, were further subjected to ADME prediction and molecular dynamic simulations, which showed promising results in terms of pharmacokinetic properties and stability. As a result, these three compounds can be considered potential HDAC6 and Hsp90 dual inhibitors and are recommended for experimental evaluation.

An Attempt of Seeking Favorable Binding Free Energy Prediction Schemes Considering the Entropic Effect on Fis-DNA Binding.

Protein-DNA binding mechanisms in a complex manner are essential for understanding many biological processes. Over the past decades, numerous experiments and calculations have analyzed the specificity of protein-DNA binding. However, the accuracy of binding free energy prediction for multi-base DNA systems still needs to be improved. Fis is a DNA-binding protein that regulates various transcription and recombination reactions. In the present work, we tested several methods of predict binding free energy based on this system to find a favorable prediction scheme and explore the binding mechanism of Fis protein and DNA. Two solvent models (explicit and implicit solvent models) were chosen for the dynamics process, and the predicted binding free energy was more accurate under the explicit solvent model. When different Poisson-Boltzmann/Generalized Born (PB/GB) models were tested for DNA force fields (BSC1 and OL15), it was found that the binding free energy predicted by the selected OL15 force field performed better and the correlation between predicted and experimental values was improved with the increasing interior dielectric constant (Dk). Finally, using Dk = 8, the GBOBC1 model combined with interaction entropy (IE), which was calculated for entropic contribution (GBOBC1_IE_8), was screened out for the binding free energy prediction and analysis of the Fis-DNA system, and the validity of the method was further verified by testing the Cren7-DNA system. By performing conformational analysis of the minor groove, it was found that mutation of the DNA central sequence A/T to C/G and deletion of the guanine 2-amino group would change the minor groove width and thus affect the formation of the major groove, altering the interaction and atomic contact between the protein and the major groove, thus changing the binding affinity of Fis and DNA. Hopefully, the series of tests in this work can shed some light on the related studies of protein and DNA systems.

Urchin-Like Structured MoO2 /Mo3 P/Mo2 C Triple-Interface Heterojunction Encapsulated within Nitrogen-Doped Carbon for Enhanced Hydrogen Evolution Reaction.

The development of highly efficient and cost-effective hydrogen evolution reaction (HER) catalysts is highly desirable to efficiently promote the HER process, especially under alkaline condition. Herein, a polyoxometalates-organic-complex-induced carbonization method is developed to construct MoO2 /Mo3 P/Mo2 C triple-interface heterojunction encapsulated into nitrogen-doped carbon with urchin-like structure using ammonium phosphomolybdate and dopamine. Furthermore, the mass ratio of dopamine and ammonium phosphomolybdate is found critical for the successful formation of such triple-interface heterojunction. Theoretical calculation results demonstrate that such triple-interface heterojunctions possess thermodynamically favorable water dissociation Gibbs free energy (ΔGH2O ) of -1.28eV and hydrogen adsorption Gibbs free energy (ΔGH* ) of -0.41eV due to the synergistic effect of Mo2 C and Mo3 P as water dissociation site and H* adsorption/desorption sites during the HER process in comparison to the corresponding single components. Notably, the optimal heterostructures exhibit the highest HER activity with the low overpotential of 69mV at the current density of 10mA cm-2 and a small Tafel slope of 60.4mV dec-1 as well as good long-term stability for 125h. Such remarkable results have been theoretically and experimentally proven to be due to the synergistic effect between the unique heterostructures and the encapsulated nitrogen-doped carbon.

Cytosporone E analogues as BRD4 inhibitors for cancer treatment: molecular docking and molecular dynamic investigations

Cancer is considered one of the worldwide life-threatening and leading causes of human mortality. In 2020, 19,292,789 cancer cases and 9,958,133 cancer deaths have been estimated worldwide. Therefore, efforts have been devoted to discover novel anticancer agents. Bromodomains have a vital role in the regulation of transcription. Many reports have shown that bromodomain-containing protein 4 (BRD4) is an important target for cancer therapeutics. In this study, several in silico approaches were utilized to discover new inhibitors against the BRD4 protein using the Schrodinger suite. A library of 27 cytosporone E derivatives was docked into the active site of the BRD4 protein. Docked ligands showed docking scores ranging between −11.289 to −3.992 Kcal/mol. Ligands 1–4 showed better binding affinities with docking scores ranging from −11.289 to −8.917 Kcal/mol compared to the reference ligand BI-2536 (−8.426 Kcal/mol). These ligands displayed favorable MM-GBSA free binding energy. Also, ligands 1–4 were subjected to molecular dynamics simulations for 100 ns to get insight into the ligand-binding stability. These compounds exhibited an average RMSD below 2.8 Å, indicating the stability of the compounds with BRD4 protein. Further, Moreover, ligands 1–3 displayed favorable AMDET properties (absorption, distribution, metabolism, excretion, and toxicity). These new compounds might be potential leads to combat cancer. Communicated by Ramaswamy H. Sarma

In silico investigation of falcipain-2 inhibition by hybrid benzimidazole-thiosemicarbazone antiplasmodial agents: A molecular docking, molecular dynamics simulation, and kinetics study.

The emergence of artemisinin-resistant variants of Plasmodium falciparum necessitates the urgent search for novel antimalarial drugs. In this regard, an in silico study to screen antimalarial drug candidates from a series of benzimidazole-thiosemicarbazone hybrid molecules with interesting antiplasmodial properties and explore their falcipain-2 (FP2) inhibitory potentials has been undertaken herein. FP2 is a key cysteine protease that degrades hemoglobin in Plasmodium falciparum and is an important biomolecular target in the development of antimalarial drugs. Pharmacokinetic properties, ADMET profiles, MM/GBSA-based binding free energies, reaction mechanisms, and associated barrier heights have been investigated. DFT, molecular dynamics simulation, molecular docking, and ONIOM methods were used. From the results obtained, four 4N-substituted derivatives of the hybrid molecule (E)-2-(1-(5-chloro-1H-benzo[d]imidazol-2-yl)ethylidene)hydrazine-1-carbothioamide (1A) denoted 1B, 1C, 1D, and 1E are drug-like and promising inhibitors of FP2, exhibiting remarkably small inhibitory constants (5.94 × 10-14 - 2.59 × 10-04 [Formula: see text]M) and favorable binding free energies (-30.32 to -17.17kcal/mol). Moreover, the ONIOM results have revealed that 1B and possibly 1C and 1D may act as covalent inhibitors of FP2. The rate-determining step of the thermodynamically favorable covalent binding mechanism occurs across a surmountable barrier height of 24.18kcal/mol in water and 28.42kcal/mol in diethyl ether. Our findings are useful for further experimental investigations on the antimalarial activities of the hybrid molecules studied.

Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

Structural basis of Nrf2 activation by flavonolignans from silymarin

Several properties of silymarin (SM) extract have been attributed to their three major flavonolignans (silybin, silychristin, and silydianin) and their 2,3-dehydro derivatives (2,3-dehydrosilybin, 2,3-dehydrosilychristin, and 2,3-dehydrosilydianin). Experimental findings have suggested that the antioxidative and protective activities of these compounds could be due to their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2). The mechanism by which SM compounds exert their effect has been suggested to be by disrupting the complex between Nrf2 and Kelch-like ECH-associated protein 1 (Keap1). However, information about the structural and energetic basis of the inhibitory mechanism of SM compounds on the Nrf2-Keap1 pathway is lacking. We evaluated the binding properties of SM compounds because experimental findings have pointed to them as potential activators of Nrf2. Our study combined docking and molecular dynamics (MD) simulations with the Poisson–Boltzmann and generalized Born and surface area (MMPBSA and MMGBSA) methods and quantum mechanics-molecular mechanics (QMMM) calculations to investigate Keap1–ligand interactions. Our results predicted that silybinA and 2,3-dehydrosilybin bind to Keap1, forming interactions with the same pockets as those observed for the cocrystallized Keap1-Cpd16 complex but with more favorable binding free energies. These findings indicate that both natural compounds are potential activators of Nrf2.

Effects of Conformational Constraint on Peptide Solubility Limits.

Liquid-liquid phase separation of proteins preferentially involves intrinsically disordered proteins or disordered regions. Understanding the solution chemistry of these phase separations is key to learning how to quantify and manipulate systems that involve such processes. Here, we investigate the effect of cyclization on the liquid-liquid phase separation of short polyglycine peptides. We simulated separate aqueous systems of supersaturated cyclic and linear GGGGG and observed spontaneous liquid-liquid phase separation in each of the solutions. The cyclic GGGGG phase separates less robustly than linear GGGGG and has a higher aqueous solubility, even though linear GGGGG has a more favorable single molecule solvation free energy. The versatile and abundant interpeptide contacts formed by the linear GGGGG stabilize the condensed droplet phase, driving the phase separation in this system. In particular, we find that van der Waals close contact interactions are enriched in the droplet phase as opposed to electrostatic interactions. An analysis of the change in backbone conformational entropy that accompanies the phase transition revealed that cyclic peptides lose significantly less entropy in this process as expected. However, we find that the enhanced interaction enthalpy of linear GGGGG in the droplet phase is enough to compensate for a larger decrease in conformational entropy.