Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor.

The calcium-sensing receptor (CaSR), abundantly expressed in the parathyroid gland and kidney, plays a central role in calcium homeostasis. In addition, CaSR exerts multimodal roles, including inflammation, muscle contraction, and bone remodeling, in other organs and tissues. The diverse functions of CaSR are mediated by many endogenous and exogenous ligands, including calcium, amino acids, glutathione, cinacalcet, and etelcalcetide, that have distinct binding sites in CaSR. However, strategies to evaluate ligand interactions with CaSR remain limited. Here, we developed a glutathione-based photoaffinity probe, DAZ-G, that analyzes ligand binding to CaSR. We showed that DAZ-G binds to the amino acid binding site in CaSR and acts as a positive allosteric modulator of CaSR. Oxidized and reduced glutathione and phenylalanine effectively compete with DAZ-G conjugation to CaSR, while calcium, cinacalcet, and etelcalcetide have cooperative effects. An unexpected finding was that caffeine effectively competes with DAZ-G's conjugation to CaSR and acts as a positive allosteric modulator of CaSR. The effective concentration of caffeine for CaSR activation (<10 µM) is easily attainable in plasma by ordinary caffeine consumption. Our report demonstrates the utility of a new chemical probe for CaSR and discovers a new protein target of caffeine, suggesting that caffeine consumption can modulate the diverse functions of CaSR.

Streamlining Computational Fragment-Based Drug Discovery through Evolutionary Optimization Informed by Ligand-Based Virtual Prescreening.

Recent advances in computational methods provide the promise of dramatically accelerating drug discovery. While mathematical modeling and machine learning have become vital in predicting drug-target interactions and properties, there is untapped potential in computational drug discovery due to the vast and complex chemical space. This paper builds on our recently published computational fragment-based drug discovery (FBDD) method called fragment databases from screened ligand drug discovery (FDSL-DD). FDSL-DD uses in silico screening to identify ligands from a vast library, fragmenting them while attaching specific attributes based on predicted binding affinity and interaction with the target subdomain. In this paper, we further propose a two-stage optimization method that utilizes the information from prescreening to optimize computational ligand synthesis. We hypothesize that using prescreening information for optimization shrinks the search space and focuses on promising regions, thereby improving the optimization for candidate ligands. The first optimization stage assembles these fragments into larger compounds using genetic algorithms, followed by a second stage of iterative refinement to produce compounds with enhanced bioactivity. To demonstrate broad applicability, the methodology is demonstrated on three diverse protein targets found in human solid cancers, bacterial antimicrobial resistance, and the SARS-CoV-2 virus. Combined, the proposed FDSL-DD and a two-stage optimization approach yield high-affinity ligand candidates more efficiently than other state-of-the-art computational FBDD methods. We further show that a multiobjective optimization method accounting for drug-likeness can still produce potential candidate ligands with a high binding affinity. Overall, the results demonstrate that integrating detailed chemical information with a constrained search framework can markedly optimize the initial drug discovery process, offering a more precise and efficient route to developing new therapeutics.

Fragment databases from screened ligands for drug discovery (FDSL-DD).

Fragment-based drug design (FBDD) is one major drug discovery method employed in computer-aided drug discovery. Due to its inherent limitations, this process experiences long processing times and limited success rates. Here we present a new Fragment Databases from Screened Ligands Drug Design method (FDSL-DD) that intelligently incorporates information about fragment characteristics into a fragment-based design approach to the drug development process. The initial step of the FDSL-DD is the creation of a fragment database from a library of docked, drug-like ligands for a specific target, which deviates from the traditional in silico FBDD strategy, incorporating structure-based design screening techniques to combine the advantages of both approaches. Three different protein targets have been tested in this study to demonstrate the potential of the created fragment library and FDSL-DD. Utilizing the FDSL-DD led to an increase in binding affinity for each protein target. The most substantial increase was exhibited by the ligand designed for TIPE2, with a 3.6 kcalmol-1 difference between the top ligand from the FDSL-DD and top ligand from the high throughput virtual screening (HTVS). Using drug-like ligands in the initial HTVS allows for a greater search of chemical space, with higher efficiency in fragments selection, less grid boxes, and potentially identifying more interactions.

Pharmacophore based virtual screening for identification of effective inhibitors to combat HPV 16 E6 driven cervical cancer.

Targeting HPV16 E6 has emerged as an effective drug target for the treatment/management of cervical cancer. We utilized pharmacophore-based virtual screening, molecular docking, absorption, distribution, metabolism and excretion (ADME) prediction, and molecular dynamics simulation approach for identifying potential inhibitors of HPV16 E6. Initially, we generated a ligand-based pharmacophore model based on the features of four known HPV16 E6 inhibitors (CA24, CA25, CA26, and CA27) via the PHASE module implanted in the Schrödinger suite. We constructed four-point pharmacophore features viz., three hydrogen bond acceptors (A) and one aromatic ring (R). The common pharmacophore feature further employed as a query for virtual screening against the ASINEX database via Schrödinger suite. The pharmacophore-based virtual screening filtered out top 2000 hits, based on the fitness score. We then applied the high throughput virtual screening (HTVS), standard precision (SP) and extra precision (XP). 1000 compounds were obtained from HTVS docking. Based on the glide score, they were further filtered to 500 hits by employing docking in standard precision mode. Finally, the best four hits and a negative molecule were identified using docking in XP mode. The four lead compounds and a negative molecule were then further subjected to ADME profile prediction by engaging Qikprop module. The ADME properties of the four lead molecules indicate good pharmacokinetic (PK) properties rather than the negative molecule. The binding stability of the HPV16 E6-hit complexes were investigated at a different time scale (100 ns) by using the desmond package and the results were examined using Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) and it revealed the stability of the protein-ligand complex throughout the simulation. Key residues, CYS 51 and GLN 107, also play a crucial role in enhancing the stability of the protein-ligand complex during the simulation. Furthermore, the binding free energy of the HPV16 E6-leads complexes was analyzed by prime which revealed that the ΔGbind coulomb and ΔGbind vdW interactions are crucially contributes to the binding affinity. In order to validate the computational findings, the efficacy of benzoimidazole and benzotriazole were ascertained for regulating ME180 cervical cancer cell survival, migration and ability to release MMP-2.

Bulk Polymerization of Acrylic Acid Using Dielectric-Barrier Discharge Plasma in a Mesoporous Material.

This research investigated a non-thermal, dielectric-barrier discharge (DBD) plasma-based approach to prepare poly(acrylic acid) (PAA) from acrylic acid in its liquid state at atmospheric temperature and pressure. Neither additives nor solvents were needed, and the polymerization was accomplished both as a film and inside a sheet of mesoporous paper. All prepared samples were characterized and the DBD plasma-initiated kinetics were analyzed for the polymerization of acrylic acid. Using FTIR semi-quantitative analysis, the degree of polymerization was monitored, and the reaction followed an overall second-order kinetic model with respect to the DBD-initiated polymerization. Additionally, the application of a PAA-modified paper as a water retention cloth or 'wet wipe' was investigated. The results showed that the PAA-modified paper substrates using DBD plasma increased water retention as a function of plasma treatment time.

A general method to predict optical rotations of chiral molecules from their structures.

The relationship of the chiroptical response of a molecule to its absolution configuration does not exist now. In this letter, I intend to report a general rule with exceptions to predict the sign of optical rotation of chiral molecules with a RCHXY structure from their absolute configurations using the Hammett constant, σ p, which is based on the electron withdrawing/donating power of functional groups. In this rule, a priority list of functional groups based on the electron withdrawing powers of the groups are used. When the lowest priority group is in the back of the molecule, a clockwise arrangement of the other three priorities from the most electron withdrawing to the least withdrawing (1-2-3) is predicted to be dextrorotatory, the counterclockwise arrangement is predicted to be levorotatory.

Surfactant-Impregnated MOF-Coated Fabric for Antimicrobial Applications.

Since the onset of the SARS-CoV-2 pandemic, the world has witnessed over 617 million confirmed cases and more than 6.54 million confirmed deaths, but the actual totals are likely much higher. The virus has mutated at a significantly faster rate than initially projected, and positive cases continue to surge with the emergence of ever more transmissible variants. According to the CDC, and at the time of this manuscript submission, more than 77% of all current US cases are a result of the B.5 (omicron). The continued emergence of highly transmissible variants makes clear the need for more effective methods of mitigating disease spread. Herein, we have developed an antimicrobial fabric capable of destroying a myriad of microbes including betacoronaviruses. We have demonstrated the capability of this highly porous and nontoxic metal organic framework (MOF), γ-CD-MOF-1, to serve as a host for varied-length benzalkonium chlorides (BACs; active ingredient in Lysol). Molecular docking simulations predicted a binding affinity of up to -4.12 kcal·mol-1, which is comparable to that of other reported guest molecules for this MOF. Similar Raman spectra and powder X-ray diffraction patterns between the unloaded and loaded MOFs, accompanied by a decrease in the Brunauer-Emmett-Teller surface area from 616.20 and 155.55 m2 g-1 respectively, corroborate the suggested potential for pore occupation with BAC. The MOF was grown on polypropylene fabric, exposed to a BAC-loading bath, washed to remove excess BAC from the external surface, and evaluated for its microbicidal activity against various bacterial and viral classes. Significant antimicrobial character was observed against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, bacteriophage, and betacoronavirus. This study shows that a common mask material (polypropylene) can be coated with BAC-loaded γ-CD-MOF-1 while maintaining the guest molecule's antimicrobial effects.

Structure-based virtual screening, in silico docking, ADME properties prediction and molecular dynamics studies for the identification of potential inhibitors against SARS-CoV-2 Mpro.

COVID-19 is a viral pandemic caused by SARS-CoV-2. Due to its highly contagious nature, millions of people are getting affected worldwide knocking down the delicate global socio-economic equilibrium. According to the World Health Organization, COVID-19 has affected over 186 million people with a mortality of around 4 million as of July 09, 2021. Currently, there are few therapeutic options available for COVID-19 control. The rapid mutations in SARS-CoV-2 genome and development of new virulent strains with increased infection and mortality among COVID-19 patients, there is a great need to discover more potential drugs for SARS-CoV-2 on a priority basis. One of the key viral enzymes responsible for the replication and maturation of SARS-CoV-2 is Mpro protein. In the current study, structure-based virtual screening was used to identify four potential ligands against SARS-CoV-2 Mpro from a set of 8,722 ASINEX library compounds. These four compounds were evaluated using ADME filter to check their ADME profile and druggability, and all the four compounds were found to be within the current pharmacological acceptable range. They were individually docked to SARS-CoV-2 Mpro protein to assess their molecular interactions. Further, molecular dynamics (MD) simulations was carried out on protein-ligand complex using Desmond at 100 ns to explore their binding conformational stability. Based on RMSD, RMSF and hydrogen bond interactions, it was found that the stability of protein-ligand complex was maintained throughout the entire 100 ns simulations for all the four compounds. Some of the key ligand amino acid residues participated in stabilizing the protein-ligand interactions includes GLN 189, SER 10, GLU 166, ASN 142 with PHE 66 and TRP 132 of SARS-CoV-2 Mpro. Further optimization of these compounds could lead to promising drug candidates for SARS-CoV-2 Mpro target.

Bacterial Biofilm Growth on 3D-Printed Materials.

Recent advances in 3D printing have led to a rise in the use of 3D printed materials in prosthetics and external medical devices. These devices, while inexpensive, have not been adequately studied for their ability to resist biofouling and biofilm buildup. Bacterial biofilms are a major cause of biofouling in the medical field and, therefore, hospital-acquired, and medical device infections. These surface-attached bacteria are highly recalcitrant to conventional antimicrobial agents and result in chronic infections. During the COVID-19 pandemic, the U.S. Food and Drug Administration and medical officials have considered 3D printed medical devices as alternatives to conventional devices, due to manufacturing shortages. This abundant use of 3D printed devices in the medical fields warrants studies to assess the ability of different microorganisms to attach and colonize to such surfaces. In this study, we describe methods to determine bacterial biofouling and biofilm formation on 3D printed materials. We explored the biofilm-forming ability of multiple opportunistic pathogens commonly found on the human body including Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus to colonize eight commonly used polylactic acid (PLA) polymers. Biofilm quantification, surface topography, digital optical microscopy, and 3D projections were employed to better understand the bacterial attachment to 3D printed surfaces. We found that biofilm formation depends on surface structure, hydrophobicity, and that there was a wide range of antimicrobial properties among the tested polymers. We compared our tested materials with commercially available antimicrobial PLA polymers.

The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-Biofilm Drugs.

Biofilm infections have no approved effective medical treatments and can only be disrupted via physical means. This means that any biofilm infection that is not addressable surgically can never be eliminated and can only be managed as a chronic disease. Therefore, there is an urgent need for the development of new classes of drugs that can target the metabolic mechanisms within biofilms which render them recalcitrant to traditional antibiotics. Persister cells within the biofilm structure may play a large role in the enhanced antibiotic recalcitrance of bacteria biofilms. Biofilm persister cells can be resistant to up to 1000 times the minimal inhibitory concentrations of many antibiotics, as compared to their planktonic envirovars; they are thought to be the prokaryotic equivalent of metazoan stem cells. Their metabolic resistance has been demonstrated to be an active process induced by the stringent response that is triggered by the ribosomally-associated enzyme RelA in response to amino acid starvation. This 84-kD pyrophosphokinase produces the "magic spot" alarmones, collectively called (p)ppGpp. These alarmones act by directly regulating transcription by binding to RNA polymerase. These transcriptional changes lead to a major shift in cellular function to both upregulate oxidative stress-combating enzymes and down regulate major cellular functions associated with growth and replication. These changes in gene expression produce the quiescent persister cells. In this work, we describe a hybrid in silico laboratory pipeline for identifying and validating small-molecule inhibitors of RelA for use in the combinatorial treatment of bacterial biofilms as re-potentiators of classical antibiotics.

Computational View toward the Inhibition of SARS-CoV-2 Spike Glycoprotein and the 3CL Protease.

Since the outbreak of the 2019 novel coronavirus disease (COVID-19), the medical research community is vigorously seeking a treatment to control the infection and save the lives of severely infected patients. The main potential candidates for the control of viruses are virally targeted agents. In this short letter, we report our calculations on the inhibitors for the SARS-CoV-2 3CL protease and the spike protein for the potential treatment of COVID-19. The results show that the most potent inhibitors of the SARS-CoV-2 3CL protease include saquinavir, tadalafil, rivaroxaban, sildenafil, dasatinib, etc. Ergotamine, amphotericin b, and vancomycin are most promising to block the interaction of the SARS-CoV-2 S-protein with human ACE-2.

Injectable and moldable hydrogels for use in sensitive and wide range strain sensing applications.

Recently, the use of hybrid double network (DN) hydrogels has become prominent due to their enhanced mechanical properties, which has opened the door for new applications of these soft materials. Only a few of these gels have demonstrated both injectable and moldable capabilities. In this work, we report the mechanical properties, gauge factor (GF) values and demonstrate both the injectability and moldability of a gelatin/polyacrylamide DN hydrogel. We optimized several parameters, such as, gelatin to polyacrylamide ratio, reactant concentrations and metal ion concentration, to produce a gelatin/polyacrylamide hydrogel with superior mechanical properties. The highest water content gel was capable of withstanding strains of 5000% before failure. These gels were facilely injected into molds where they effectively changed shape and maintained similar properties prior to remolding. When 20 mM calcium was doped into a similar gel, a tensile strength of 1.71 MPa was achieved. Aside from improving the mechanical properties of the gels, both Ca2+ and Mg2+ also improved their conductivity, so they were tested for use as strain sensors. The sensitivity of the hydrogel strain sensors were measured using the GF. For the 20 mM Ca2+ hydrogel, these GF values ranged from 1.63 to 6.85 for strains of 100% to 2100% respectively. Additionally, the sensors showed good stability over continuous cyclic stretching, demonstrating their long term reliability for strain sensing.

A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease.

BACKGROUND: The COVID-19 has now been declared a global pandemic by the World Health Organization. There is an emergent need to search for possible medications. METHOD: Utilization of the available sequence information, homology modeling, and in slico docking a number of available medications might prove to be effective in inhibiting the SARS-CoV-2 two main drug targets, the spike glycoprotein, and the 3CL protease. RESULTS: Several compounds were determined from the in silico docking models that might prove to be effective inhibitors for SARS-CoV-2. Several antiviral medications: Zanamivir, Indinavir, Saquinavir, and Remdesivir show potential as and 3CLPRO main proteinase inhibitors and as a treatment for COVID-19. CONCLUSION: Zanamivir, Indinavir, Saquinavir, and Remdesivir are among the exciting hits on the 3CLPRO main proteinase. It is also exciting to uncover that Flavin Adenine Dinucleotide (FAD) Adeflavin, B2 deficiency medicine, and Coenzyme A, a coenzyme, may also be potentially used for the treatment of SARS-CoV-2 infections. The use of these off-label medications may be beneficial in the treatment of the COVID-19.

Applications of Highly Stretchable and Tough Hydrogels.

Stretchable and tough hydrogels have drawn a lot of attention recently. Due to their unique properties, they have great potential in the application in areas such as mechanical sensing, wound healing, and drug delivery. In this review, we will summarize recent developments of stretchable and tough hydrogels in these areas.

High Electron Mobility of Amorphous Red Phosphorus Thin Films.

Black phosphorus (BP) has been gathering great attention for its electronic and optoelectronic applications due to its high electron mobility and high ION/OFF current switching ratio. The limitations of this material include its low synthetic yield and high cost. One alternative to BP is another type of phosphorus allotrope, red phosphorus (RP), which is much more affordable and easier to process. Although RP has been widely used in industry for hundreds of years and considered as an insulating material, in this study, we demonstrate through field-effect transistors (FET) measurements that amorphous red phosphorus (a-RP) films are semiconductive with a high mobility of 387 cm2 V-1 s-1 and a current switching ratio of ≈103 , which is comparable to the electronic characteristics previously reported for BP. The films were produced via a thermal evaporation method or a facile drop-casting approach onto Si/SiO2 substrates. We also report a study of the oxidation process of the films over time and a method to stabilize the films via doping a-RP with metal oxides. The doped films retain stability for one thousand I-V cycles, with no signs of degradation.

Multifunctionalized polyethersulfone membranes with networked submicrogels to improve antifouling property, antibacterial adhesion and blood compatibility.

Intensive efforts have been employed in modifying biomedical membranes. Among them, blending is recognized as a simple method. However, the conventional blending materials commonly lead to an insufficient modification, which is mainly caused by the poor miscibility between the blending materials and the matrixes, the elution of the hydrophilic materials from the matrixes during the use and storage, and the insufficient surface enrichment of the blending materials. Aiming to solve the abovementioned disadvantages, we developed novel polyethersulfone/poly(acrylic acid-co-N-vinyl-2-pyrrolidone) networked submicrogels (PES/P(AA-VP) NSs), which were blended with PES to enhance the antifouling properties, antibacterial adhesion and haemocompatible properties of PES membranes. As results, the PES/P(AA-VP) NSs showed good miscibility with the PES matrix, and hydrophilic submicrogels would enrich onto the membrane surface during the phase inversion process due to the surface segregation. The entanglement between the PES matrix and the networked submicrogels would effectively limit the elution of the submicrogels. In conclusion, the modified PES membranes prepared by blending with the PES/P(AA-VP) NSs might draw great attention for the application in haemodialysis fields.

Photoactivated Polymeric Bilayer Actuators Fabricated via 3D Printing.

4D printing is an emerging additive manufacturing technology that combines the precision of 3D printing with the versatility of smart materials. 4D printed objects can change their shape over time with the application of a stimulus (i.e., heat, light, moisture). Light driven smart materials are attractive because light is wireless, remote, and can induce a rapid shape change. Herein, we present a method for fabricating polymeric bilayer actuators via 3D printing which reversibly change their shape upon exposure to light. The photoactive layer consists of a poly(siloxane) containing pendant azobenzene groups. Two different photoactive polymers were synthesized, and the photomechanical effect displayed by the bilayers was evaluated. These bilayers exhibit rapid actuation with full cycles completed within seconds, and photo generated stresses ranging from 1.03 to 1.70 MPa.

Engineering of hemocompatible and antifouling polyethersulfone membranes by blending with heparin-mimicking microgels.

To improve the hemocompatibility and antifouling property of polyethersulfone (PES) membranes, heparin-mimicking microgels of poly(acrylic acid-co-N-vinyl-2-pyrrolidone) (P(AA-VP)) and poly(2-acrylamido-2-methylpropanesulfonic acid-co-acrylamide) (P(AMPS-AM)) were synthesized by conventional free radical copolymerization, and then incorporated into a PES matrix by blending. The results of Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and scanning electron microscopy (SEM) confirmed that heparin-mimicking microgels were successfully synthesized. The presence of the microgels in the membrane matrix was also confirmed by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), thermogravimetric analysis (TGA), and SEM. Compared with pristine PES membranes, the improvement of the antifouling property of the heparin-mimicking microgel modified membranes was demonstrated by the increased flux recovery ratio and improved anti-bacterial adhesion, while the enhancement of hemocompatibility for the modified membranes was proved by the decreased plasma protein adsorption, suppressed platelet adhesion, prolonged clotting times, as well as depressed blood-related complement activation. Additionally, after introducing the heparin-mimicking microgels, the membranes showed enhanced cell adhesion and proliferation properties. These results indicated that the heparin-mimicking microgel modified membranes had great potential to be used as blood contacting materials.

Ultrasensitive Detection of Cu2+ Using a Microcantilever Sensor Modified with L-Cysteine Self-Assembled Monolayer.

A microcantilever was modified with a self-assembled monolayer (SAM) of L-cysteine for the sensitively and selectively response to Cu(II) ions in aqueous solution. The microcantilever undergoes bending due to sorption of Cu(II) ions. The interaction of Cu(II) ions with the L-cysteine on the cantilever is diffusion controlled and does not follow a simple Langmuir adsorption model. A concentration of 10-10 M Cu(II) was detected in a fluid cell using this technology. Other cations, such as Ni2+, Zn2+, Pb2+, Cd2+, Ca2+, K+, and Na+, did not respond with a significant deflection, indicating that this L-cysteine-modified cantilever responded selectively and sensitively to Cu(II).

Suitability of N-propanoic acid spiropyrans and spirooxazines for use as sensitizing dyes in dye-sensitized solar cells.

This work deals with the fabrication and evaluation of color-changing dye-sensitized solar cells (DSSCs) that include N-propanoic acid-functionalized spiropyrans and spirooxazines as sensitizing dyes. We investigated the photophysical properties of these compounds in various solvents and pH conditions using UV-Vis spectroscopy, and their behavior on TiO2 photoanode surfaces using a combination of UV-Vis and FT-IR. Their performance as sensitizing dyes for DSSCs was also analyzed. This study revealed a number of unique properties for this class of compounds that affect their performance as both photochromic compounds and DSSC sensitizers, which allow for future creation of efficient photochromic DSSCs.