MLASM: Machine learning based prediction of anticancer small molecules.

Cancer, being the second leading cause of death globally. So, the development of effective anticancer treatments is crucial in the field of medicine. Anticancer peptides (ACPs) have shown promising therapeutic potential in cancer treatment compared to traditional methods. However, the process of identifying ACPs through experimental means is often time-intensive and expensive. To overcome this issue, we employed a machine learning-based approach for the first time to develop an anticancer model using small molecules. Anticancer small molecules (ACSMs) are compounds that have been developed to target and inhibit cancer cells. In this study, we used 10,000 compounds to develop the machine learning models using five algorithms such as, Random Forest (RF), Light gradient boosting machine (LightGBM), K-nearest neighbors (KNN), Decision tree (DT) and Extreme Gradient Boosting (XGB). The developed models were evaluated using the test set and top three models were identified (RF, LightGBM and XGB). Furthermore, to validate the predictive performance of our models, we have performed external validation using an FDA approved anticancer compounds/drugs. Following this analysis, we found that our LightGBM model correctly predicted 9 compounds as active. However, RF and XGB exhibited some limitations by predicting 8 and 7 compounds as active out of 10, respectively. These results demonstrate that, when compared to RF and XGB, the LightGBM model showcase robust prediction capabilities, achieving a superior accuracy of 79% with an AUC of 0.88. These findings provide promising insights into the potential of our approach for predicting anticancer small molecules, highlighting the role of machine learning in advancing cancer treatment research.

Structure and dynamics of the somatostatin receptor 3-ligand binding in the presence of lipids examined using computational structural biology methods.

In the past two decades, the structural biology studies on G-protein coupled receptors (GPCRs) are on the rise. Understanding the relation between the structure and function of GPCRs is important as they play a huge role in various signaling mechanisms in a eukaryotic cell. Somatostatin receptor 3 (SSTR3), one of the GPCRs, is one such important receptor which oversees different cellular processes including cell-to-cell signaling. However, the information available regarding the structural features of SSTR3 responsible for their bioactivity is scarce. In this study, we report a structural understanding of SSTR3-ligand binding that could be helpful in demystifying the structural complexities related to functioning of the receptor. An integrated protocol consisting of different computational structural biology tools including protein structure prediction via comparative modeling, binding site characterization, three-dimensional quantitative structure-activity relationship based on comparative molecular field analysis and comparative molecular similarity indices analysis, density functional theory, and molecular dynamics simulations were performed. Different understandings from the simulation of SSTR3-ligand complexes, mainly the conditions that are favorable for the formation of lowest bioactive state of SSTR3 ligands are reported. In addition to that, we report the important physicochemical descriptors of SSTR3 ligands that could significantly influence their bioactivity. The results of the study could be helpful in developing novel SSTR3 ligands (both agonists and antagonists) with high potency and receptor selectivity.

A Novel Chemical Gas Vapor Sensor Based on Photoluminescence Enhancement of Rugate Porous Silicon Filters.

In this study, an innovative rugate filter configuration porous silicon (PSi) with enhanced photoluminescence intensity was fabricated. The fabricated PSi exhibited dual optical properties with both sharp optical reflectivity and sharp photoluminescence (PL), and it was developed for use in organic vapor sensing. When the wavelength of the resonance peak from the rugate PSi filters is engineered to overlap with the emission band of the PL from the PSi quantum dots, the PL intensity is amplified, thus reducing the full width at half maximum (FWHM) of the PL band from 154 nm to 22 nm. The rugate PSi filters samples were fabricated by electrochemical etching of highly doped n-type silicon under illumination. The etching solution consisted of a 1:1 volume mixture of 48% hydrofluoric acid and absolute ethanol and photoluminescent rugate PSi filter was fabricated by etching while using a periodic sinusoidal wave current with 10 cycles. The obtained samples were characterized by scanning electron microscopy (SEM), and both reflection redshift and PL quenching were measured under exposure to organic vapors. The reflection redshift and PL quenching were both affected by the vapor pressure and dipole moment of the organic species.

1,3,5-Trinitrotoluene Sensor Based on Silole Nanoaggregates.

Bis(methyltetraphenyl)silole and bis(methyltetraphenyl)silole siloxane nanoaggregates for the detection of TNT were developed by using aggregation-induced emission property. Their absolute quantum yields and critical water concentration for onset of aggregation were measured. Average particle size for both nanoaggregates were measured and tuned by controlling the water fraction by volume. Absolute quantum yield of both nanoaggregates in 90% water volume fraction increased by more than 40 times. Detection of TNT was achieved from the quenching PL measurement of both nanoaggregates by adding the TNT. A linear Stern-Volmer relationship was observed for the detection of TNT.

Detection of Human Ig G Using Photoluminescent Porous Silicon Interferometer.

Photoluminescent porous silicon (PSi) interferometers having dual optical properties, both Fabry-Pérot fringe and photolumincence (PL), have been developed and used as biosensors for detection of Human Immunoglobin G (Ig G). PSi samples were prepared by electrochemical etching of p-type silicon under white light exposure. The surface of PSi was characterized using a cold field emission scanning electron microscope. The sensor system studied consisted of a single layer of porous silicon modified with Protein A. The system was probed with various fragments of aqueous human immunoglobin G (Ig G) analyte. Both reflectivity and PL were simultaneously measured under the exposure of human Ig G. An increase of optical thickness and decrease of PL were obtained under the exposure of human Ig G. Detection limit of 500 fM was observed for the human Ig G.

Easy Synthesis and Characterization of Poly(alkoxysilane)s Promoted by Silver-Platinum Mixed Complexes.

One-pot Si-Si/Si-O dehydrocoupling of hydrosilanes with alcohols (1:1.5 mole ratio), promoted by a mixture of AgNO3-H2PtCl6 (150/1 mole ratio) readily gave poly(alkoxysilane)s in good yield (62-91%). The addition of small amount of platinum complex to form nanoparticles facilitated the silicon polymer formation when compared to the reaction rate with AgNO3 alone. The primary/secondary hydrosilanes [p-X-C6H4SiH3 (X = H, CH3, OCH3, F), PhCH2SiH3, and (PhSiH2)2] and alcohols [MeOH, EtOH, (i)PrOH, PhOH, and CF3(CF2)2CH2OH] were used for the reaction. The weight average molecular weight and polydispersity of the poly(alkoxysilane)s were in the range of 1,690-7,100 Dalton and 1.44-3.49, respectively. The reaction of phenylsilane with ethanol (1:3 mole ratio) using the Ag-Pt complexes produced triethoxyphenylsilane only, as expected. The reaction of phenylsilane with Ge-132 produced an insoluble cross-linked gel.

Anisotropic multi-spot DBR porous silicon chip for the detection of human immunoglobin G.

Asymmetric porous silicon multilayer (APSM)-based optical biosensor was developed to specify human Immunoglobin G (Ig G). APSM chip was generated by an electrochemical etching of silicon wafer using an asymmetric electrode configuration in aqueous ethanolic HF solution and constituted with nine arrayed porous silicon multilayer. APSM prepared from anisotropic etching conditions displayed a sharp reflection resonance in the reflectivity spectrum. Each spot displayed single reflection resonance at different wavelengths as a function of the lateral distance from the Pt counter electrode. The sensor system was consisted of the 3 x 3 spot array of APSM modified with protein A. The system was probed with an aqueous human Ig G. Molecular binding and specificity was monitored as a shift in wavelength of reflection resonance.

Synthesis and characterization of phosphine/borane-terminated poly(silole-co-germole) for the evaluation of luminescent polymer light-emitting diode.

Codehydrocoupling (using Red-Al) followed by borane/phosphine-capping (with Ph2BCl and Ph2PCl) of 1,1-dihydrotetraphenylsilole (1) and 1,1-dihydrotetraphenylgermole (2) (9:1 mole ratio) gave electroluminescent poly(silole-co-germole)s containing borane/phosphine-ends (3, 4) in high yield. The borane-terminated copolymer 3 emits at 522 nm and are electroluminescent at 521 nm. The fluorescence quantum yield of 3 in toluene is (1.60±0.30) x 10(-2). The phosphine-terminated copolymer 4 emits at 520 nm and are electroluminescent at 520 nm. The fluorescence quantum yield of 4 in toluene is (1.60±0.20) x 10(-2). 3 and 4 were then mixed in 1:1 ratio. The emission color of 3/4 mixture is green and the maximum brightness of the device is 2,760 cd/m2 with a luminous efficiency of 0.67 lm/W. The borane/phosphine end groups in the 1:1 mixture of 3 and 4 exhibited no appreciable effect on the luminescent properties in spite of possible B-P dative bonding. Ge-132 helped to increase the B-P dative bonding. The electroluminescent copolymers 3 and 4 are good candidates for PLED (polymer light-emitting diode) fabrication.

Repurposing FDA-approved compounds to target JAK2 for colon cancer treatment.

Colorectal cancer is one of the common cancers worldwide and the second leading cause of cancer-related death. The current treatment has the inherent drawbacks and there is a need of developing a new treatment. Interleukin-6 a pleiotropic cytokine involved in immune regulation and activation of JAK2/STAT3 pathway in colorectal cancer. JAK2/STAT3 signaling pathway functions as a critical regulator of cell growth, differentiation, and immune expression. The abnormality in the JAK2/STAT3 pathway is involved in the tumorigenesis of colon cancer including apoptosis. In this study, we identified novel inhibitors for JAK2 protein by performing virtual screening against FDA-approved compounds. To address the selectivity issue, we implemented cross-docking method followed by DFT calculations to understand the chemical reactivity of the identified compounds. Additionally, molecular dynamics (MD) simulations were performed for the top FDA compounds against JAK2 to understand the molecular interactions and structural stability of the complex over a period of 200 ns. Our results indicated that ergotamine, entrectinib, exatecan, dihydroergotamine, and paritaprevir can be used as alternative drugs for colon cancer. In addition, ergotamine was found to efficiently lower the cell viability with IC50 values of 100 µM on colon cancer cell lines. The long-term inhibitory effect of the ergotamine led to a decrease in colony size, and the toxicity properties were studied using hemolysis assay. Our study shows the potential of targeting JAK2 as a novel approach to colon cancer treatment, and demonstrate that ergotamine as a promising effects as an anti-cancer drug.

Inhibitory effects of a new 1H-pyrrolo[3,2-c]pyridine derivative, KIST101029, on activator protein-1 activity and neoplastic cell transformation induced by insulin-like growth factor-1.

Diarylureas and diarylamides derivatives are reported to have antitumor activity. Encouraged by the interesting antiproliferative activity of diarylurea and diarylamide derivatives, we synthesized a new series of diarylureas and diarylamides containing pyrrolo[3,2-c]pyridine scaffold. In this study, we demonstrate that a N-(3-(4-benzamido-1H-pyrrolo[3,2-c]pyridin-1-yl)phenyl)-4-morpholino-3-(trifluoromethyl)benzamide, KIST101029, inhibits neoplastic cell transformation induced by insulin-like growth factor 1 (IGF-1) in mouse epidermal JB6 Cl41 cells. The KIST101029 compound inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinases (MEK), c-jun N-terminal kinases (JNK), and mechanistic target of rapamycin (mTOR) signaling pathways induced by IGF-1 in JB6 Cl41 cells, resulting in the inhibition of c-fos and c-jun transcriptional activity. In addition, the KIST101029 inhibited the associated activator protein-1 (AP-1) transactivation activity and cell transformation induced by IGF-1 in JB6 Cl41 cells. Consistent with these observations, in vivo chorioallantoic membrane assay also showed that the KIST101029 inhibited IGF-1-induced tumorigenicity of JB6 Cl41 cells. Importantly, KIST101029 suppressed the colony formation of A375 cells in soft agar. Taken together, these results indicate that a KIST101029 might exert chemopreventive effects through the inhibition of phosphorylation of MAPK and mTOR signaling pathway.

Porous silicon platform for optical detection of functionalized magnetic particles biosensing.

The physical properties of porous materials are being exploited for a wide range of applications including optical biosensors, waveguides, gas sensors, micro capacitors, and solar cells. Here, we review the fast, easy and inexpensive electrochemical anodization based fabrication porous silicon (PSi) for optical biosensing using functionalized magnetic particles. Combining magnetically labeled biomolecules with PSi offers a rapid and one-step immunoassay and real-time detection by magnetic manipulation of superparamagnetic beads (SPBs) functionalized with target molecules onto corresponding probe molecules immobilized inside nano-pores of PSi. We first give an introduction to electrochemical and chemical etching procedures used to fabricate a wide range of PSi structures. Next, we describe the basic properties of PSi and underlying optical scattering mechanisms that govern their unique optical properties. Finally, we give examples of our experiments that demonstrate the potential of combining PSi and magnetic beads for real-time point of care diagnostics.

Fabrication and characterization of photoluminescent silicon nanoparticles for drug delivery applications.

Photoluminescent silicon nanoparticles containing camptothecin (CPT) were fabricated by using a CPT-derivatized porous silicon (PSi). PSi samples displaying red photoluminescence (PL) were prepared by an electrochemical etch of n-type silicon under the illumination with a 300 W tungsten filament bulb for the duration of etch. For the drug-derivatized PSi, luminescent PSi was oxidized and derivatized with CPT. Silicon nanoparticles containing CPT were obtained by fracturing of luminescent PSi with ultrasono-method. Optical characteristic of drug-derivatized silicon particles were investigated in aqueous buffer solution. The release of CPT was measured by UV-vis spectrometer. The intensity of fluorescence of the silicon nanoparticles was measured with a drug release. The concentration of released drug exhibited non-linear relationship with a release time.

Adsorption and desorption characteristics of gradient distributed Bragg reflector porous silicon layers.

Adsorption and desorption characteristics of gradient distributed Bragg reflector (DBR) porous silicon (PSi) were investigated under the exposure of organic vapors. Gradient DBR PSi whose average pore size decreased as the lateral distance from the Pt electrode increased was generated by using an asymmetric etching configuration. The reflection resonances were measured as a function of lateral distance from a point closest to the plate Pt electrode to a position on the silicon surface. Two types of gradient DBR PSi (H- and HO-terminated gradient DBR PSi) were used in this study. The detection of volatile organic compounds (VOCs) using the gradient DBR PSi had been achieved. When the vapor of VOCs condensed in the nanopores, the gradient DBR PSi modified with hydrophobic and hydrophilic functionality exhibited different pore adsorption and desorption characteristics.

Synthesis and optical characterization of silicon nanoparticles.

Various reaction conditions, such as quantity of reducing agent and reaction time were investigated with the aim of finding a simple, optimized synthetic route for the synthesis of luminescent silicon nanoparticles (SiNPs). Si NPs were synthesized from the reaction of ethylenediammonium chloride and magnesium silicide via a low temperature solution route. Optical characterizations of silicon nanoparticles were achieved by using ultraviolet-visible (UV-Vis) and photoluminescence (PL) spectroscopy. As the reaction time longer, silicon nanoparticles grew and their emission wavelength shifted to the longer wavelength. The monotonic shift of the photoluminescence as a function of excitation wavelength resulted in the excitation of different sizes of nanocrystals that had different optical transition energies.

Facile synthesis and characterization of silver nanoparticle/bis(o-phenolpropyl)silicone composites using a gold catalyst.

The generation of silver nanoparticle/bis(o-phenolpropyl)silicone composites have been facilitated by the addition of sodium tetrachloroaurate or gold(Ill) chloride (< 1 wt% of NaAuCl4 or AuCl3) to the reaction of silver nitrate (AgNO3) with bis(o-phenolpropyl)silicone [BPPS, (o-phenolpropyl)2(SiMe2O)n, n = 2,3,8,236]. TEM and FE-SEM data showed that the silver nanoparticles having the size of < 20 nm are well dispersed throughout the BPPS silicone matrix in the composites. XRD patterns are consistent with those for polycrystalline silver. The size of silver nanoparticles augmented with increasing the relative molar concentration of AgNO3 added with respect to BPPS. The addition of gold complexes (1-3 wt%) did not affect the size distribution of silver nanoparticles appreciably. In the absence of BPPS, the macroscopic precipitation of silver by agglomeration, indicating that BPPS is necessary to stabilize the silver nanoparticles surrounded by coordination.

One-pot synthesis and structural characterization of poly(alkoxysilane)s catalyzed by silver-gold complexes.

Combinative one-pot Si-Si/Si-O dehydrocoupling of hydrosilanes with alcohols (1:1.5 mole ratio), mediated by a mixture of AgNO3-AuCl3 (100/1 mole ratio) rapidly produced poly(alkoxysilane)s in reasonably high yield. The addition of small amount of gold complex to the reaction mixture effectively accelerated the coupling reaction compared to the reaction rate with AgNO3 alone. The hydrosilanes include p-X-C6H4SiH3 (X = H, CH3, OCH3, F), PhCH2SiH3, and (PhSiH2)2. The alcohols include MeOH, EtOH, iPrOH, PhOH, and CF3(CF2)2CH2OH. The weight average molecular weight and polydispersity of the poly(alkoxysilane)s were in the range of 1,600-8,000 Dalton and 1.4-3.5, respectively. The dehydrocoupling reactions of phenylsilane with ethanol (1:3 mole ratio) in the presence of the Ag-Au complexes gave only triethoxyphenylsilane.

Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators.

Introduction: Kinesin family member 5A (KIF5A) is a motor neuron protein expressed in neurons and involved in anterograde transportation of organelles, proteins, and RNA. Variations in the KIF5A gene that interfere with axonal transport have emerged as a distinguishing feature in several neurodegenerative disorders, including hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), and Amyotrophic Lateral Sclerosis (ALS). Methods: In this study, we implemented a computational structural and systems biology approach to uncover the role of KIF5A in ALS. Using the computational structural biology method, we explored the role of non-synonymous Single Nucleotide Polymorphism (nsSNPs) in KIF5A. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS. Results: We found KIF5AS291F variant showed the most structure destabilizing behavior and the phytocompound "epigallocatechin gallate" showed the highest binding affinity (-9.0 Kcal/mol) as compared to wild KIF5A (-8.4 Kcal/mol). Further, with the systems biology approach, we constructed the KIF5A protein-protein interaction (PPI) network to identify the associated Kinesin Families (KIFs) proteins, modules, and their function. We also constructed a transcriptional and post-transcriptional regulatory network of KIF5A. With the network topological parameters of PPIN (Degree, Bottleneck, Closeness, and MNC) using CytoHubba and computational knock-out experiment using Network Analyzer, we found KIF1A, 5B, and 5C were the significant proteins. The functional modules were highly enriched with microtubule motor activity, chemical synaptic transmission in neurons, GTP binding, and GABA receptor activity. In regulatory network analysis, we found KIF5A post-transcriptionally down-regulated by miR-107 which is further transcriptionally up-regulated by four TFs (HIF1A, PPARA, SREBF1, and TP53) and down-regulated by three TFs (ZEB1, ZEB2, and LIN28A). Discussion: We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and KIF5A associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases.

Detection of nitroaromatic compounds based on phenylethylene-derivatized porous silicon.

Nanocrystalline porous silicon (PSi) surfaces have been used to detect nitroaromatic compounds in vapor phase. The mode of photoluminescence (PL) is emphasized as a sensing attitude or detection technique. Quenching of PL from nanocrystalline porous surfaces as a transduction mode is measured upon the exposure of nitroaromatic compounds. To verify the detection of explosives, the surface of PSi is functionalized with different groups. The quenching mechanism of PL is attributed to the electron transfer behaviors of quantum-sized nano-crystallites in the PSi matrix to the analytes (nitroaromatics). An attempt has been done to prove that the surface-derivatized photoluminescent PSi surfaces can act as versatile substrates for sensing behaviors due to having a large surface area and highly sensitive transduction mode.

Fabrication of human IgG sensors based on porous silicon interferometer containing Bragg structures.

A simply modified biosensor based on protein A-modified distributed Bragg reflectors (DBR) porous silicon (PSi) chip for the detection of human immunoglobin G (IgG) are developed. The fabrication, optical characterization, and surface derivatization of DBR PSi are investigated. The sensor system studied consist of multi-layer of porous silicon modified with protein-A. The sensor is operated by the measurement of the reflection peak in the white light reflection spectrum. Molecular binding is detected as a shift in wavelength of reflection peaks.

Synthesis and characterization of silver nanoparticle composite with poly(p-Br-phenylsilane).

The one-pot synthesis and characterization of silver nanoparticle-poly(p-Br-phenylsilane) composites have been carried out. The conversion of silver(+1) salt to stable silver(0) nanoparticles is promoted by poly(p-Br-phenylsilane), Br-PPS possessing both possible reactive Si-H bonds in the polymer backbone and C-Br bonds in the substituents. The composites were characterized using XRD, TEM, FE-SEM, and solid-state UV-vis analytical techniques. TEM and FE-SEM data show the formation of the composites where large number of silver nanoparticles (less than 30 nm of size) are well dispersed throughout the Br-PPS matrix. XRD patterns are consistent with that for fcc-typed silver. The elemental analysis for Br atom and the polymer solubility confirm that the cleavage of C-Br bond and the Si-Br dative bonding were not occurred appreciably at ambient temperature. Nonetheless, TGA data suggest that some sort of cross-linking was occurred at high temperature. The size and processability of such nanoparticles depend on the ratio of metal to Br-PPS. In the absence of Br-PPS, most of the silver particles undergo macroscopic aggregation, which indicates that the polysilane is necessary for stabilizing the silver nanoparticles.