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.

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.

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.

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.

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.

Growth of 2D black phosphorus film from chemical vapor deposition.

Phosphorene, a novel 2D material isolated from bulk black phosphorus (BP), is an intrinsic p-type material with a variable bandgap for a variety of applications. However, these applications are limited by the inability to isolate large films of phosphorene. Here we present an in situ chemical vapor deposition type approach that demonstrates progress towards growth of large area 2D BP with average areas >3 µm2 and thicknesses representing samples around four layers and thicker samples with average areas >100 µm2. Transmission electron microscopy and Raman spectroscopy have confirmed successful growth of 2D BP from red phosphorus.

Ultra-Long Crystalline Red Phosphorus Nanowires from Amorphous Red Phosphorus Thin Films.

Heating red phosphorus in sealed ampoules in the presence of a Sn/SnI4 catalyst mixture has provided bulk black phosphorus at much lower pressures than those required for allotropic conversion by anvil cells. Herein we report the growth of ultra-long 1D red phosphorus nanowires (>1 mm) selectively onto a wafer substrate from red phosphorus powder and a thin film of red phosphorus in the present of a Sn/SnI4 catalyst. Raman spectra and X-ray diffraction characterization suggested the formation of crystalline red phosphorus nanowires. FET devices constructed with the red phosphorus nanowires displayed a typical I-V curve similar to that of black phosphorus and a similar mobility reaching 300 cm(2) V(-1) s with an Ion /Ioff ratio approaching 10(2) . A significant response to infrared light was observed from the FET device.

Structure-based drug design of diphenyl α-aminoalkylphosphonates as prostate-specific antigen antagonists.

Here, we describe the mechanism of diphenyl α-aminoalkylphosphonate ester derivatives as potent inhibitors of prostate-specific antigen (PSA), a likely protease responsible for the advancement of prostate tumor progression. The AutoDock 4.2 molecular docking suite was utilized to model covalent and noncovalent binding of this class of inhibitors to predict crystallographic poses and compare experimental IC50 dose-response curves and in silico potencies for providing future more specific rational drug design. The new lead compound R/S-diphenyl[N-benzyloxycarbonylamino(4-carbamoylphenyl)methyl]phosphonate is being reported in this study as a potent inhibitor of PSA activity (IC50 = 250 nM; AutoDock Score = -8.29/-9.14 kJ·mol(-1) for R/S). Molecular dynamics (MD) simulations using GROMACS 4.6.5 was used to obtain trajectories of the top ligand and validate key interactions in the binding complex. A hydrogen-bonding map was used to confirm interactions between the lead compound and residues THR190, SER217, and SER227 in the P1 pocket. The modeling study introduces novel aminoalkylphosphonates as a potential drug candidate for targeting PSA by optimizing P1 binding affinities.

Highly stable polyaniline-poly(sodium 4-styrenesulfonate) nanoparticles for sensing of amines.

Sensing technology is the key of intelligent packaging. A variety of different sensing systems for indicating freshness through intelligent packaging have been presented. Polyaniline (PANI) can change its color reversibly through the acid-base reaction with reactive compounds and has been widely used in different kinds of sensors. However, because PANI is insoluble in common organic solvents, this limits its practical usage in many applications. In this work, a highly stable polyaniline-poly(sodium 4-styrenesulfonate) (PANI:PSS) colloid has been developed as a facile colorimetric sensor of volatile amines. The results showed the PANI:PSS colloid is quite sensitive to changes in pH. When PANI:PSS colloids were homogenously deposited on filter paper, the paper are used as a sensor to detect triethylamine (TEA) vapor. The green color of the test paper changed to blue at a TEA concentration as low as 188 ppm.

Perylenetetracarboxylic diimide (PTCDI) nanowires for sensing ethyl acetate in wine.

We report the application of perylenetetracarboxylic diimide (PTCDI) nanowires for sensing ethyl acetate. The conductivity of the crystalline nano/microwires increases quickly and selectively in the presence of ethyl acetate vapor, but not with water, acid and alcohol vapors, suggesting that the nanowires of PTCDI may be used for monitoring ethyl acetate during a wine manufacturing process.

Highly sensitive and selective fluoride ion sensors based on microcantilevers modified with hydrogels.

We have developed two microcantilever sensors, one modified with chitosan/gelatin hydrogels doped with CH3(OCH2CH2)3OTBDPS and another modified with chitosan-OTBDPS/gelatin hydrogels, for the sensitive and selective detection of fluoride ions (F-) in aqueous solution. Upon exposure to F-, the microcantilevers underwent bending deflection due to the cleavage of Si-O bond on reacting with F- in the hydrogel. The results show that the maximum bending deflections are proportional to the concentrations of F-, and the limits of detection are 10(-8) M and 10(-9) M for the two microcantilevers, respectively. Other ions, such as Cl-, Br-, NO3-, H2PO4-, HSO4-, and AcO- have little effect on the deflection of the microcantilevers. The results show that the microcantilever may be used for in situ quantitative detection of F- in an aqueous solution and the mechanism of the bending are discussed.

Enhancing Selectivity with Molecularly Imprinted Polymers via Non-Thermal Dielectric Barrier Discharge Plasma.

Molecularly imprinted polymers (MIPs) are synthetic polymers that mimic the functions of antibodies. Though MIPs are promising tools in various areas, achieving high selectivity in MIPs can be difficult. To improve selectivity, various approaches have been implemented; however, the role of polymerization methods or synthetic techniques in enhancing the selectivity of MIPs has not been studied and remains a crucial area for further research. MIPs are typically prepared from free radical reactions. Recently, we found that Dielectric Barrier Discharge (DBD) plasma can be used to initiate the polymerization of vinyl monomers. The DBD plasma method allows the monomers to associate with the template molecules and initiate polymerization with minimal disruption to the positioning of the monomers. We hypothesize that this could be a preferred method to prepare MIPs over the traditional radical reaction that may cause a disturbance of the pre-associated monomers on the templates for the polymerization. Chicken egg white serum albumin (CESA) was used as the template protein for the MIPs. Our results show that in all test conditions, approximately twofold improvement in selectivity was achieved, which is the primary performance metric for MIPs. This enhancement was evident across all categories, including MIPs prepared from various monomer combinations.

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.

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.

Rapid and sensitive detection of maize chlorotic mottle virus using surface plasmon resonance-based biosensor.

We report a biosensor based on surface plasmon resonance (SPR) for the selective detection of maize chlorotic mottle virus (MCMV). 11-Mercaptoundecanoic acid was applied on a gold surface to form a self-assembled monolayer, and a layer of anti-MCMV antibody was crosslinked on the surface for specific recognition of MCMV. The effects of coupling reaction time and antibody concentration on detection sensitivity were studied. The coverage mass change is a function of the concentration of MCMV with a dynamic range from 1 to 1000 ppb. The detection limit is approximately 1 ppb, which is approximately two orders of magnitude higher than that of the existing enzyme-linked immunosorbent assay (ELISA) method. The developed SPR sensor showed highly specific recognition for both purified MCMV and crude extracts from real-world samples.

The effect of oxygen vacancies on water wettability of a ZnO surface.

In this study, the effect of oxygen vacancies on the water wettability of a hydrated ZnO(100) surface has been examined via molecular dynamics simulations with a reactive force field (ReaxFF). The results show that the oxygen vacancies on the ZnO surface change the structures of the ZnO surface and subsequently its water adsorption capability. While a 1 : 1 ratio of water to hydroxyl is observed for a water monolayer absorbed on ZnO(100) without oxygen vacancies, additional water adsorption as coordinate hydroxyl that resides on the vacancy site and bonds with three lattice zinc atoms is observed on the surfaces with oxygen vacancies. The results also show that the energy of the interaction per unit area between water and the hydrated ZnO surface is 55.1% higher in the presence of the oxygen vacancies than that without oxygen vacancies. This leads to a water contact angle of ~115° for the hydrated ZnO(100) surface in the absence of vacancies and ~21° with vacancies. The wetting kinetics of a water droplet on a ZnO(100) surface with and without oxygen vacancies are compared with the diffusion-limited reactive wetting and molecular kinetics models, respectively. In addition, the ordering of the vacancy sites is found not to significantly affect the wettability of the ZnO(100) surface.

Strong resistance of (tridecafluoro-1,1,2,2-tetrahydrooctyl)triethoxysilane (TTS) nanofilm to protein adsorption.

In this report, the properties of fluorocarbon-containing (tridecafluoro-1,1,2,2-tetrahydrooctyl)triethoxysilane (TTS) (C14 H19 F13 O3 Si) nanofilm coated on silicon surface and its potential to resist protein adsorption were examined. Thickness and wettability of the silicon surface before and after TTS nanofilm coating were examined by ellipsometry and contact angle goniometry, respectively. The same techniques were used to examine protein layer on nonmodified and TTS-coated silicon surface. In addition, bright-field optical microscopy and fluorescence spectrophotometry were used to provide visual, qualitative description of adsorbed proteins and the specific signal of fluorescence-labeled bovine serum albumin (BSA), respectively, on bare and TTS-coated silicon surface. Single-component protein solution of four model proteins, namely BSA, human fibrinogen, bovine serum immunoglobulin G, and fibronectin, was prepared, and the adsorption responses of these four proteins on TTS nanofilm were examined, using nonmodified silicon surface as comparison. TTS substantially reduces the adsorption of all four proteins tested. Our results indicate that fluorocarbon-containing TTS, once coated on surfaces, is an effective molecule for resisting protein adsorption. This will open up potential applications, particularly for silicon-containing implant devices such as glass.

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.

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.

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.