Molecular Modeling Approach Research Articles

Discovery of imidazopyridine derived oxadiazole-based thiourea derivatives as potential anti-diabetic agents: Synthesis, in vitro antioxidant screening and in silico molecular modeling approaches

A series of new imidazopyridine based oxadiazole derivatives (5a-l) were designed and synthesized. Their structures were confirmed by spectral data and then subjected to in vitro assessment including α-glucosidase, α-amylase inhibitory, and 2- diphenyl-1-picrylhydrazyl (DDPH) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities. The inhibitory activity results revealed that all the synthesized analogs displayed significant α-glucosidase and α-amylase inhibition with IC50 values of 0.90 ± 0.10 to 18.10 ± 0.20 µM (for α-glucosidase) and 1.10 ± 0.10 to 19.70 ± 0.20 µM (for α-amylase) respectively as compared to standard acarbose with IC50 values of 11.50 ± 0.30 µM (α-glucosidase) and 12.20 ± 0.30 µM (for α-amylase).The synthesized analogs also showed significant DPPH and ABTS radical scavenging activities with IC50 values in the range of 1.05 ± 0.05 to 4.56 ± 3.12 µM (for DDPH) and 1.15 ± 0.05 to 4.89 ± 2.89 µM (for ABTS) respectively, incomparison to standard ascorbic acid with IC50 = 1.83 ± 1.32 µM (for DDPH) and 1.84 ± 1.16 µM (for ABTS) respectively. After crucial analysis of varying substitution effects on inhibitory (α-glucosidase &α-amylase) and radical scavenging (DPPH & ABTS) potentials respectively, the structure-activity relationship (SAR) was established. Through the in silico molecular docking analysis, the ability of the synthesized analogs to inhibit α-glucosidase and α -amylase was also examined.There was a good correlation between in vitro and in silico studies for synthesized analogs 5i and 5d Further studies are required to determine whether these potent analogs could be a potential treatment for diabetes disease.

Synthesis, Characterization, Theoretical and Experimental Anticancer Evaluation of Novel Cocrystals of 5-Fluorouracil and Schiff Bases against SW480 Colorectal Carcinoma.

The chemotherapeutic agent known as 5-fluorouracil (5-FU) is an artificial fluoropyrimidine antimetabolite that has been widely used for its antineoplastic properties. Cocrystals of 5-fluorouracil (5-FU) with five different Schiff bases (benzylidene-urea (BU), benzylidene-aniline (BA), salicylidene-aniline (SA), salicylidene-phenylhydrazine (SPH), and para-hydroxy benzylideneaniline (HBA)) are reported in this study. The newly synthesized cocrystals were analyzed by FTIR and PXRD. In this study, we investigated the antitumor efficacy of 5-FU derivatives in SW480 colon cancer cells via MTT assay at varying dose concentrations. Molecular docking was performed to predict the binding mechanism of TS with various 5-FU complexes. FTIR revealed the presence of respective functional groups in the prepared cocrystals. The frequencies (v) of N-H (3220.24 cm-1) and carbonyl groups (1662.38 cm-1) in the spectrum of 5-FU shifted considerably in all derivative cocrystal new interactions. There was a noticeable transformation in the PXRD peak of 5-FU at 2θ = 28.37° in all derivatives. The novelty of the present study lies in the fact that 5-FU-BA showed an anticancer potential IC50 (6.4731) far higher than that of 5-FU (12.116), almost comparable to that of the reference drug doxorubicin (3.3159), against SW480 cancel cell lines, followed by 5-Fu-HBA (10.2174). The inhibition rates of 5-FU-BA and 5-FU-HBA were highest among the derivatives (99.85% and 99.37%, respectively) in comparison with doxorubicin (97.103%). The results revealed that the synthesized 5-FU cocrystals have promising antitumor efficacy compared with previously reported 5-FU and 5-FU. The activities of the cocrystals were rationalized by a molecular modeling approach to envisage binding modes with the target cancer protein.

Inhibitory effect of Nifedipine on aldose reductase delays cataract progression.

Aldose reductase (ALR2) is a rate-limiting component of the polyol pathway, which is essential for the NADPH-mediated conversion from glucose to sorbitol. ALR2 dysregulation has been linked to α-crystallin aggregation, increased oxidative stress, and calcium inflow, all of which contribute to a diabetic cataract. Given its crucial role in occular pathologies, ALR2 has emerged as a promising target to treat oxidative stress and hyperglycaemic condition which form the underlying cause of diabetic cataracts. However, several of them had issues with sensitivity and specificity to ALR2, despite being screened as effective ALR2 inhibitors from a wide range of structurally varied molecules. The current study investigates the inhibitory potential of Nifedipine, an analog of the dihydro nicotinamide class of compounds against ALR2 activity. The enzyme inhibition studies were supported by in vitro biomolecular interactions, molecular modeling approaches, and in vivo validation in diabetic rat models. Nifedipine demonstrated appreciable inhibitory potential with the purified recombinant hAR (human aldose reductase; with an IC50 value of 2.5µM), which was further supported by Nifedipine-hAR binding affinity (Kd = 2.91 ± 1.87 × 10-4M) by ITC and fluorescence quenching assays. In the in vivo models of STZ-induced diabetic rats, Nifedipine delayed the onset progression of cataracts by preserving the antioxidant enzyme activity (SOD, CAT, and GPX GSH, TBARS, and protein carbonyls) and was shown to retain the α-crystallin chaperone activity by reducing the calcium levels in the diabetic rat lens. In conclusion, our results demonstrate effective inhibition of ALR2 by Nifedipine, resulting in amelioration of diabetic cataract conditions by lowering oxidative and osmotic stress while retaining the chaperone activity of α-crystallins. The present study could be envisaged to improve the eye condition in older adults upon Nifedipine treatment.

Investigation of Molecular Interactions Mechanism of Pembrolizumab and PD-1.

Human programmed cell death protein 1 (PD-1) is a checkpoint protein involved in the regulation of immune response. Antibodies are widely used as inhibitors that block the immune checkpoint, preventing strong immune responses. Pembrolizumab is an FDA-approved IgG4 antibody with PD-1 inhibitory ability for the treatment of melanoma. In this study, we investigated the effect of Pembrolizumab on the conformational changes in PD-1 using extensive molecular modeling and simulation approaches. Our study revealed that during the 200 ns simulation, the average values of the solvent accessible surface area, the radius of gyration, and internal hydrogen bonds of PD-1 were 64.46 nm2, 1.38 nm and 78, respectively, while these values of PD-1 in the PD-1/Pembrolizumab complex were 67.29 nm2, 1.39 nm and 76, respectively. The RMSD value of PD-1 gradually increased until 80 ns and maintained its stable conformation at 0.32 nm after 80 ns, while this value of PD-1 in the PD-1/Pembrolizumab complex maintained an increasing trend during 200 ns. The interaction between PD-1 and Pembrolizumab led to a flexible but stable structure of PD-1. PD-1 rotated around the rotation axis of the C'D loop and gradually approached Pembrolizumab. The number of hydrogen bonds involved in the interactions on the C and C' strands increased from 4 at 100 ns to 7 at 200 ns. The strong affinity of Pembrolizumab for the C'D and FG loops of PD-1 disrupted the interactions between PD-1 and PD-L1. Inhibition of the interaction between PD-1 and PD-L1 increased the T cell activity, and is effective in controlling and curing cancer. Further experimental work can be performed to support this finding.

Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation.

Direct oral anticoagulants are an important and relatively new class of synthetic anticoagulant drugs commonly used for the pharmacotherapy of thromboembolic disorders. However, they still have some limitations and serious side effects, which continuously encourage medicinal chemists to search for new active compounds acting as human-activated coagulation factor X (FXa) inhibitors. Isosteviol is a nontoxic hydrolysis product of naturally occurring stevioside and possesses a wide range of therapeutic properties, including anticoagulant activity. The present contribution describes the in silico design of novel oxime ether isosteviol derivatives as well as a molecular modeling approach based on QSAR analysis and a docking simulation for searching for novel isosteviol-based compounds as potential FXa inhibitors. The elaborated ANN model, encompassing topological and geometrical information, exhibited a significant correlation with FXa-inhibitory activity. Moreover, the docking simulation indicated six of the most promising isosteviol-like compounds for further investigation. Analysis showed that the most promising derivatives contain heterocyclic, aromatic, five-membered moieties, with substituents containing chlorine or fluorine atoms. It is anticipated that the findings reported in the present work may provide useful information for designing effective FXa inhibitors as anticoagulant agents.

Non-Canonical Amino Acids as Building Blocks for Peptidomimetics: Structure, Function, and Applications.

This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely distributed in nature and are known to enhance the stability of specific secondary structures and/or biological function. Contrary to the ubiquitous DNA-encoded amino acids, the structure and function of these residues are not fully understood. Here, results from experimental and molecular modelling approaches are gathered to classify several classes of non-canonical amino acids according to their ability to induce specific secondary structures yielding different biological functions and improved stability. Regarding side-chain modifications, symmetrical and asymmetrical α,α-dialkyl glycines, Cα to Cα cyclized amino acids, proline analogues, β-substituted amino acids, and α,β-dehydro amino acids are some of the non-canonical representatives addressed. Backbone modifications were also examined, especially those that result in retro-inverso peptidomimetics and depsipeptides. All this knowledge has an important application in the field of peptidomimetics, which is in continuous progress and promises to deliver new biologically active molecules and new materials in the near future.

Physiological activation of human and mouse bitter taste receptors by bile acids

Beside the oral cavity, bitter taste receptors are expressed in several non-gustatory tissues. Whether extra-oral bitter taste receptors function as sensors for endogenous agonists is unknown. To address this question, we devised functional experiments combined with molecular modeling approaches to investigate human and mouse receptors using a variety of bile acids as candidate agonists. We show that five human and six mouse receptors are responsive to an array of bile acids. Moreover, their activation threshold concentrations match published data of bile acid concentrations in human body fluids, suggesting a putative physiological activation of non-gustatory bitter receptors. We conclude that these receptors could serve as sensors for endogenous bile acid levels. These results also indicate that bitter receptor evolution may not be driven solely by foodstuff or xenobiotic stimuli, but also depend on endogenous ligands. The determined bitter receptor activation profiles of bile acids now enable detailed physiological model studies.

Identification of potent histone deacetylase 2 (HDAC2) inhibitors through combined structure and ligand-based designs and molecular modelling approach

Histone deacetylase 2 (HDAC2) is associated with various neuropathic degenerative diseases and is considered a novel target for Alzheimer’s disease (AD). Elevated levels of HDAC2 trigger excitatory neurotransmission and reduce synaptic plasticity, synaptic number, and memory formation. In the current study, we identified HDAC2 inhibitors using an integrated structure and ligand-based approaches to drug design. Three pharmacophore models were generated by using different pharmacophoric features and validated using the Enrichment factor (EF), Güner-henry (GH) score, and percentage yield. The model of choice was used to screen a library of Zinc-15 compounds and interfering compounds were eliminated by using drug likeliness and PAINS filtering. Further, docking studies in three stages were carried out to obtain hits with good binding energies and were followed by ADMET studies yielding three virtual hits. The virtual hits, i.e. ZINC000008184553, ZINC0000013641114, and ZINC000032533141, were subjected to molecular dynamics simulation studies. Compound ZINC000008184553, identified as lead, was found to have optimal stability, low toxicity under simulated conditions, and may potentially inhibit HDAC2. Communicated by Ramaswamy H. Sarma

Integrated molecular modeling and dynamics approaches revealed potential natural inhibitors of NF-κB transcription factor as breast cancer therapeutics

Breast cancer is a silent killer malady among women and a serious economic burden in health care management. A case of breast cancer is diagnosed among women every 19 s, and every 74 s, a woman dies of breast cancer somewhere in the world. Despite the pop-up of progressive research, advanced treatment approaches, and preventive measures, breast cancer remains amplifying ailment. The nuclear factor kappa B (NF-κB) is a key transcription factor that links inflammation with cancer and is demonstrated as being involved in the tumorigenesis of breast cancer. The NF-κB transcription factor family in mammals consists of five proteins; c-Rel, RelA(p65), RelB, NF-κB1(p50), and NF-κB2(p52). The antitumor effect of NF-κB has also been explored in breast cancer, however, the actual treatment for breast cancer is yet to be discovered. This study is attributed to the identification of novel drug targets against breast cancer by targeting c-Rel, RelA(p65), RelB, NF-κB1(p50), and NF-κB2(p52) proteins. To identify the putative active compounds, a structure-based 3D pharmacophore model to the protein active site cavity was generated followed by virtual screening, molecular docking, and molecular dynamics (MD) simulation. Initially, a library of 45000 compounds were docked against the target protein and five compounds namely Z56811101, Z653426226, Z1097341967, Z92743432, and Z464101066 were selected for further analysis. The relative binding affinity of Z56811101, Z653426226, Z1097341967, Z92743432, and Z464101066 with NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel proteins were −6.8, −8, −7.0, −6.9, and −7.2 kcal/mol, respectively which remained stable throughout the simulations of 200 ns. Furthermore, all of these compounds depict maximum drug-like properties. Therefore, the proposed compounds can be a potential candidate for patients with breast cancer, but, experimental validation is needed to ensure their safety. Communicated by Ramaswamy H. Sarma

Design and synthesis of a new bifunctional chelating agent: Application for Al 18F/177Lu complexation

Theranostic and personalized medicine are blooming strategies to improve oncologic patients' health care and facilitate early treatment. While 18F-radiochemistry for theranostic application is attractive due to its imaging properties, combining diagnosis by positron emission tomography (PET) via aluminum-fluoride-18 and β− therapy with lutetium-177 is relevant. Nevertheless, it requires the use of two different chelating agents, which are NOTA and DOTA for aluminum-fluoride-18 and lutetium-177 radiolabeling, respectively. To overcome this issue, we propose herein the synthesis of a new hybrid chelating agent named NO2A-AHM, which can be labeled with different types of emitters (β+, β− and γ) using the mismatched Al18F/177Lu pair. NO2A-AHM, is based on a hydrazine moiety functionalized by a NOTA cycle, a chelating arm, and a linker with a maleimide function. This design is chosen to increase the flexibility and allow the formation of 5 up to 7 coordination bonds with metal ions. Moreover, this agent can be coupled to targeting moieties containing a thiol function, such as peptides, to increase selectivity towards specific cancer cells. Experimental complexation and computational chemistry studies are performed to confirm the capacity of our chelating agent to label both aluminum-fluoride and lutetium using molecular modeling approaches at Density Functional Theory (DFT) level.The proof of concept of the ability of NO2A-AHM to complex both aluminum-fluoride-18, for PET imaging applications, and lutetium-177 for radiotherapy has shown encouraging results which is prominent for the development of a fully consistent theranostic approach.

Discovery of the allosteric inhibitor from actinomyces metabolites to target EGFRCSTMLR mutant protein: molecular modeling and free energy approach

EGFR (epidermal growth factor receptor), a surface protein on the cell, belongs to the tyrosine kinase family, responsible for cell growth and proliferation. Overexpression or mutation in the EGFR gene leads to various types of cancer, i.e., non-small cell lung cancer, breast, and pancreatic cancer. Bioactive molecules identified in this genre were also an essential source of encouragement for researchers who accomplished the design and synthesis of novel compounds with anticancer properties. World Health Organization (WHO) report states that antibiotic resistance is one of the most severe risks to global well-being, food safety, and development. The world needs to take steps to lessen this danger, such as developing new antibiotics and regulating their use. In this study, 6524 compounds derived from Streptomyces sp. were subjected to drug-likeness filters, molecular docking, and molecular dynamic simulation for 1000 ns to find new triple mutant EGFRCSTMLR (EGFR-L858R/T790M/C797S) inhibitors. Docking outcomes revealed that five compounds showed better binding affinity (− 9.074 to − 9.3 kcal/mol) than both reference drug CH7233163 (− 6.11 kcal/mol) and co-crystallized ligand Osimertinib (− 8.07 kcal/mol). Further, molecular dynamic simulation confirmed that ligand C_42 exhibited the best interaction at the active site of EGFR protein and comprised a better average radius of gyration (3.87 Å) and average SASA (Solvent Accessible Surface Area) (82.91 Å2) value than co-crystallized ligand (4.49 Å, 222.38 Å2). Additionally, its average RMSD (Root Mean Square Deviation) (3.25 Å) and RMSF (Root Mean Square Fluctuation) (1.54 Å) values were highly similar to co-crystallized ligand (3.07 Å, 1.54 Å). Compared to the reference ligand, it also demonstrated conserved H-bond interactions with the residues MET_793 and GLN_791 with strong interaction probability. In conclusion, we have found a potential drug with no violation of the rule of three, Lipinski's rule of five, and 26 other vital parameters having great potential in medicinal and pharmaceutical industries applications and can overcome synthetic drug issues.

HR-LCMS and evaluation of anti-diabetic activity of Hemidesmus indicus (anantmool): Kinetic study, and molecular modelling approach

This study delved into the exploration of novel antidiabetic medications acquired from natural resources, utilizing the Ayurvedic Rasayana herb Hemidesmus indicus through cutting-edge chemoprofiling and molecular modelling techniques. The methanolic extract of Hemidesmus indicus root exhibited the highest extractive yield (24.70 ± 0.08 %) and contained substantial levels of total phenolic and flavonoid content as 154.15 ± 1.24 mg Gallic Acid Equivalent/g extract and 70.61 ± 0.35 Quercetin Equivalent/g extract respectively. Invitro study revealed the potent inhibitory potential of methanolic extract of the herb against essential carbohydrate hydrolytic enzymes α-amylase (IC50 = 4.19 ± 0.04 mg/ml) and α-glucosidase (IC50 = 5.78 ± 0.10 mg/ml). Further, the enzyme kinetic study demonstrated the competitive mode of inhibition of both enzymes. HR-LCMS analysis identified the major phytoconstituents present in the extracts, including Solanocapsine, Cyclovirobuxine C, Lucidine B, Zygadenine, Aspidospermidine, silychristin, 3beta-3-Hydroxy-18-lupen-21-one, Manglupenone, and 19-Noretiocholanolone. Molecular docking, molecular dynamic simulation, and MM/GBSA analysis have proved stable, rigid, compact, and folded form of complexes during the entire 100 ns simulation, illustrating Zygadenine, Solanocapsine, and Cyclovirobuxine C as the superior inhibitors of α-A protein, while Zygadenine, Plumieride, and Phlegmarine exhibited greater inhibitory behaviour towards α-G protein than the FDA-approved drug acarbose. Collectively, our findings indicate that the Hemidesmus indicus could be a promising source of α-A and α-G inhibitors, potentially serving as a lead in order to develop medications for type-2 diabetes.

Immunomodulatory potential of bioactive glycoside syringin: a network pharmacology and molecular modeling approach

Many diseases, such as rheumatoid arthritis, neurodegenerative disease, lupus, autoimmune disease, and cancer, are described by chronic inflammation following tissue damage. Anti-inflammatory drugs like non-steroidal anti-inflammatory drugs and other steroids cause many side effects and generally need careful consideration and monitoring during usage. In recent years, a significant interest in plant-derived approaches has been warranted. The bioactive glycoside syringin might be one of the effective immunomodulatory agents. However, its immunomodulatory potential needs to be better known. In this study, we evaluated the immunomodulatory potential of syringin using network pharmacology, molecular docking, and molecular dynamics simulation-based approaches. First, we applied the GeneCards and OMIM databases to acquire the immunomodulatory agents. Then, the STRING database was utilized to get the hub genes. Interaction analysis and molecular docking described strong binding of the active site of immunomodulatory proteins with the bioactive syringin. Molecular dynamics simulations (200 ns) showed a very stable interaction of syringin with the immunomodulatory protein. Further, the optimized structure and molecular electrostatic potential of the syringin were calculated by a density-functional theory utilizing basis levels of B3LYP/6-31. Syringin investigated in this study holds the required drug-likeness characteristics and follows Lipinski’s rule of five. However, quantum-chemical estimations show the syringin has potent reactivity, demonstrating a lower energy gap. Furthermore, the gap between ELUMO and EHOMO was low, suggesting the excellent affinity of syringin towards the immunomodulatory proteins. The present study shows that syringin might be an effective immunomodulatory agent and can be further explored using different experimental methods. Communicated by Ramaswamy H. Sarma

Molecular insights into the inhibition of early stages of Aβ peptide aggregation and destabilization of Alzheimer's Aβ protofibril by dipeptide D-Trp-Aib: A molecular modelling approach

Amyloid beta (Aβ) peptide aggregates rapidly into the soluble oligomers, protofibrils and fibrils to form senile plaques, a neurotoxic component and pathological hallmark of Alzheimer's disease (AD). Experimentally, it has been demonstrated the inhibition of an early stages of Aβ aggregation by a dipeptide D-Trp-Aib inhibitor, but its molecular mechanism is still unclear. Hence, in the present study, we used molecular docking and molecular dynamics (MD) simulations to explore the molecular mechanism of inhibition of an early oligomerization and destabilization of preformed Aβ protofibril by D-Trp-Aib. Molecular docking study showed that the D-Trp-Aib binds at the aromatic (Phe19, Phe20) region of Aβ monomer, Aβ fibril and hydrophobic core of Aβ protofibril. MD simulations revealed the binding of D-Trp-Aib at the aggregation prone region (Lys16-Glu22) resulted in the stabilization of Aβ monomer by π-π stacking interactions between Tyr10 and indol ring of D-Trp-Aib, which decreases the β-sheet content and increases the α-helices. The interaction between Lys28 of Aβ monomer to D-Trp-Aib could be responsible to block the initial nucleation and may impede the fibril growth and elongation. The loss of hydrophobic contacts between two β-sheets of Aβ protofibril upon binding of D-Trp-Aib at the hydrophobic cavity resulted in the partial opening of β-sheets. This also disrupts a salt bridge (Asp23-Lys28) leading to the destabilization of Aβ protofibril. Binding energy calculations revealed that van der Waals and electrostatic interactions maximally favours the binding of D-Trp-Aib to Aβ monomer and Aβ protofibril respectively. The residues Tyr10, Phe19, Phe20, Ala21, Glu22, Lys28 of Aβ monomer, whereas Leu17, Val18, Phe19, Val40, Ala42 of protofibril contributing for the interactions with D-Trp-Aib. Thus, the present study provides structural insights into the inhibition of an early oligomerization of Aβ peptides and destabilization of Aβ protofibril, which could be useful to design novel inhibitors for the treatment of AD.

Application of an Integrative Drug Safety Model for Detection of Adverse Drug Events Associated With Inhibition of Glutathione Peroxidase 1 in Chronic Obstructive Pulmonary Disease

BackgroundChronic Obstructive Pulmonary Disease is characterised by declining lung function and a greater oxidative stress burden due to reduced activity of antioxidant enzymes such as Glutathione Peroxidase 1.ObjectivesThe extent to which drugs may contribute to this compromised activity is largely unknown. An integrative drug safety model explores inhibition of Glutathione Peroxidase 1 by drugs and their association with chronic obstructive pulmonary disease adverse drug events.MethodsIn silico molecular modelling approaches were utilised to predict the interactions that drugs have within the active site of Glutathione Peroxidase 1 in both human and bovine models. Similarities of chemical features between approved drugs and the known inhibitor tiopronin were also investigated. Subsequently the Food and Drug Administration Adverse Event System was searched to uncover adverse drug event signals associated with chronic obstructive pulmonary disease.ResultsStatistical and molecular modelling analyses confirmed that the use of several registered drugs, including acetylsalicylic acid and atenolol may be associated with inhibition of Glutathione Peroxidase 1 and chronic obstructive pulmonary disease.ConclusionThe integration of molecular modelling and pharmacoepidemological data has the potential to advance drug safety science. Ongoing review of medication use and further pharmacoepidemiological and biological analyses are warranted to ensure appropriate use is recommended.Graphical

Comparison between the intermolecular interactions in the liquid and solid forms of propellant 1,1,1,2 – Tetrafluoroethane

A multitude of metered dose inhaler (MDI) formulation properties, such as permanent particle growth or separation, can affect the device’s drug delivering performance. 1,1,1,2 – Tetrafluoroethane (HFA-134a) is a liquid propellant commonly employed in MDIs. Here molecular modelling approaches are reported to evaluate the effect weak hydrogen bonding and steric repulsions have on its solid and liquid state molecular-scale structure. Molecular dynamics (MD) simulations of pure liquid HFA-134a were completed for a range of temperatures (203 – 323 K) and intermolecular interactions were analysed using the molecular trajectory files generated. Empirical force fields were used to calculate the strength of interactions seen in the low-temperature crystal structure, and these were compared to the liquid.The solid-state intermolecular structure arranges to maximise attractive interactions between permanent dipoles which enables the formation of ‘weak hydrogen bonds’, these were found to guide the transition from body centred cubic to its low temperature, monoclinic phase. Reducing HFA-134a’s liquid phase temperature increases its resemblance to the believed body centred cubic structure, with improved similarity between intermolecular radial distribution functions and vector angles. Weak hydrogen bonds in the liquid occurred more frequently at lower temperatures but the minimisation of steric repulsions is identified as the main cause of structural ordering, this shows liquid propellant is relatively non-polar. Understanding the structure of pure propellant is useful when evaluating the variation in wetting between different formulation materials and has the potential to be a useful resource for digital drug product design.

Multicriteria design of novel natural hydrophobic deep eutectic solvents for the extraction of perfluoroalkyl acids using COSMO-RS

In this study, a molecular modeling approach was used to identify the most effective natural hydrophobic deep eutectic solvents (HDESs) for extracting the emerging pollutants, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) from synthetic wastewater. The use of HDESs for this purpose has not been reported in the literature, making this a pioneering contribution to the field. First, an extensive literature search was conducted to generate a list of 74 non-ionic HDES constituents. In the second step, a systematic screening of natural components was conducted to identify 55 new compounds that can be used for the synthesis of HDESs. The Conductor-like Screening Model for Real Solvents (COSMO-RS) was then used to screen the 129 potential HDES constituents based on three key performance indicators: distribution ratio, selectivity, and performance index at infinite dilution compared to the predicted performance of toluene as a benchmark, as the use of molecular solvents or DESs for this purpose has never been reported in the literature. The top 20 HDES constituents with the highest extraction performance were predominantly from the terpene and terpenoid families. The median lethal dose was also used to analyze toxicity. A multicriteria evaluation approach was adopted to evaluate several properties important to liquid–liquid extraction (LLE) processes, including the extraction performance, density, vapor pressure, water solubility, and leachability of DESs. Three HDESs, namely, trioctylphosphine oxide: 2-methylbenzothiazole (1:9), trioctylphosphine oxide: menthyl acetate (1:4), and 1,8-cineole: menthyl acetate (2.5:1), showed promising results. This study provides molecular insights on extracting PFOA/PFOS from wastewater using HDESs and emphasizes the need to evaluate LLE units using multicriteria. In addition, the results may serve as a starting point for further research, including the synthesis and characterization of novel HDES constituents and the development of optimized HDESs for the extraction of PFOA/PFOS from wastewater.

Cover Image, Volume 124, Number 5, May 2023

Front Cover: The cover image is based on the Research Article Drug repurposing for Mpox: Discovery of small molecules as potential inhibitors against DNA-dependent RNA polymerase using molecular modeling approach by Mansi Dutt et al., https://doi.org/10.1002/jcb.30397.

Structural vaccinology-based design of multi-epitopes vaccine against Streptococcus gordonii and validation using molecular modeling and immune simulation approaches

Streptococcus gordonii is an oral bacterium colonizing the dental cavity and leading to plaque formation. This pervasive colonizer is also the etiologic agent of bacterial endocarditis and has a major role in infective endocarditis. The bacteria reach the heart through oral bleeding, leading to inflammation of cardiovascular valves. Over the past 50 years, it has shown a significant pathogenic role in immunocompromised and neutropenic patients. Since antibiotic resistance has created prophylaxis failure towards infective endocarditis, a potent therapeutic candidate is needed. Therefore, multi-epitopes vaccine offers advantages over the other approaches. Thus, herein, numerous molecular-omics tools were exploited to mine immunogenic peptides, i.e., T-cell and B-cell epitopes, and construct a vaccine sequence. Our findings revealed a total of 24 epitopes, including CTL, HTL, and B-cell are responsible for imparting immune responses, which were combined with the help of different linkers, and MEVC was constructed. Multifactorial validation of the candidate vaccine was performed to minimize the risk factors. The final sequence was docked with TLR2 to validate its conformation compatibility with receptor and long-term interactions stability. Our analysis revealed that the vaccine construct is immunogenic and non-allergenic. The construct also established various contacts with the immune receptor. Finally, the vaccine sequence was reverse-translated, optimized for codon usage, and analyzed for expression in the Escherichia coli K12 strain. Maximum expression was noted with a CAI score of 0.95. In silico immune simulation revealed that the antigen was neutralized on the 3rd day after injection. In conclusion, the current study warrants validation of the vaccine construct both in in vitro and in vivo models for accurate therapeutic intervention.

Selective killing of the human gastric pathogen Helicobacter pylori by mitochondrial respiratory complex I inhibitors

Respiratory complex I is a multicomponent enzyme conserved between eukaryotic cells and many bacteria, which couples oxidation of electron donors and quinone reduction with proton pumping. Here, we report that protein transport via the Cag type IV secretion system, a major virulence factor of the Gram-negative bacterial pathogen Helicobacter pylori, is efficiently impeded by respiratory inhibition. Mitochondrial complex I inhibitors, including well-established insecticidal compounds, selectively kill H.pylori, while other Gram-negative or Gram-positive bacteria, such as the close relative Campylobacter jejuni or representative gut microbiota species, are not affected. Using a combination of different phenotypic assays, selection of resistance-inducing mutations, and molecular modeling approaches, we demonstrate that the unique composition of the H.pylori complex I quinone-binding pocket is the basis for this hypersensitivity. Comprehensive targeted mutagenesis and compound optimization studies highlight the potential to develop complex I inhibitors as narrow-spectrum antimicrobial agents against this pathogen.