Predicting ground vibration during rock blasting using relevance vector machine improved with dual kernels and metaheuristic algorithms.

The ground vibration caused by rock blasting is an extremely hazardous outcome of the blasting operation. Blasting activity has detrimental effects on both the ecology and the human population living in proximity to the area. Evaluating the magnitude of blasting vibrations requires careful evaluation of the peak particle velocity (PPV) as a fundamental and essential parameter for quantifying vibration velocity. Therefore, this study employs models using the relevance vector machine (RVM) approach for predicting the PPV resulting from quarry blasting. This investigation utilized the conventional and optimized RVM models for the first time in ground vibration prediction. This work compares thirty-three RVM models to choose the most efficient performance model. The following conclusions have been mapped from the outcomes of the several analyses. The performance evaluation of each RVM model demonstrates each model achieved a performance of more than 0.85 during the testing phase, there was a strong correlation observed between the actual ground vibrations and the predicted ones. The analysis of performance metrics (RMSE = 21.2999 mm/s, 16.2272 mm/s, R = 0.9175, PI = 1.59, IOA = 0.8239, IOS = 0.2541), score analysis (= 93), REC curve (= 6.85E-03, close to the actual, i.e., 0), curve fitting (= 1.05 close to best fit, i.e., 1), AD test (= 11.607 close to the actual, i.e., 9.790), Wilcoxon test (= 95%), Uncertainty analysis (WCB = 0.0134), and computational cost (= 0.0180) demonstrate that PSO_DRVM model MD29 outperformed better than other RVM models in the testing phase. This study will help mining and civil engineers and blasting experts to select the best kernel function and its hyperparameters in estimating ground vibration during rock blasting project. In the context of the mining and civil industry, the application of this study offers significant potential for enhancing safety protocols and optimizing operational efficiency.

Design and synthesis of novel and potent allosteric HIV-1 integrase inhibitors with a spirocyclic moiety.

We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.

Design and synthesis of novel fluorene derivatives as inhibitors of pyruvate dehydrogenase kinase.

Activation of pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDHK) has the potential for the treatment of diabetes mellitus and its complications, caused by the malfunction of the glycolytic system and glucose oxidation. In this paper, we describe the identification of novel PDHK inhibitors with a fluorene structure. High-throughput screening using our in-house library provided compound 6 as a weak inhibitor that occupied the allosteric lipoyl group binding site in PDHK2. Structure-based drug design (SBDD) while addressing physicochemical properties succeeded in boosting inhibitory activity approximately 700-fold. Thus obtained compound 32 showed favorable pharmacokinetics profiles supported by high membrane permeability and metabolic stability, and exhibited activation of PDH in rat livers and a glucose lowering effect in Zucker fatty rats.

Soft ground micro TBM jack speed and torque prediction using machine learning models through operator data and micro TBM-log data synchronization.

Tunnel Boring Machines (TBMs) are pivotal in underground projects like subways, highways, and water supply tunnels. Predicting and monitoring jack speed and torque is crucial for optimizing TBM excavation efficiency. Conventionally, skilled operators manually adjust numerous tunnelling parameters to regulate the machine's progress. In contrast, machine learning (ML) algorithms offer a promising avenue where computers learn from operator actions to establish parameter relationships autonomously. This study introduces an innovative approach to enhancing operator monitoring and TBM data comprehension. A robust correlation between TBM operator behaviour and TBM logged data is established by leveraging an Optuna-assisted ML methodology-the research light on the intricate dynamics influencing TBM advance rate parameters. Operational data is collected from micro slurry tunnel boring machine (MSTBM) umbrella support excavations. The proposed framework harnesses Optuna, an advanced hyperparameter optimization platform, to dynamically refine jack speed and torque settings. Through meticulous analysis of the interplay between TBM operator decisions and real-time logged data, the AI model discerns patterns, empowering informed decision-making. Using Optuna, a range of models, including random forest (RF), K-nearest neighbours (kNN), decision tree (DT), XGBoost, Support Vector Machine (SVM), and Artificial Neural Network (ANN) were automatically compared and tuned. The best model's (RF) performance is evaluated through a correlation coefficient (R2) of 96%, mean squared error (MSE) of 119.7, and mean absolute error (MAE) of 4.42 for jack speed decision making while 83% of R2, MSE of 0.62, and MAE of 0.42 for the torque decision making. This intelligent model can assist the TBM operator in making decisions about TBM control.

Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitors.

In research focused on protein-protein interaction (PPI) inhibitors, the optimization process to achieve both high inhibitory activity and favorable physicochemical properties remains challenging. Our previous study reported the discovery of novel and bioavailable Keap1-Nrf2 PPI inhibitor 8 which exhibited moderate in vivo activity in rats. In this work, we present our subsequent efforts to optimize this compound. Two distinct approaches were employed, targeting high energy water molecules and Ser602 as "hot spots" from the anchor with good aqueous solubility, metabolic stability, and membrane permeability. Through ligand efficiency (LE)-guided exploration, we identified two novel inhibitors 22 and 33 with good pharmacokinetics (PK) profiles and more potent in vivo activities, which appear to be promising chemical probes among the existing inhibitors.

Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Screening approaches for the identification of Nrf2-Keap1 protein-protein interaction inhibitors targeting hot spot residues.

Protein-protein interactions (PPIs) play a crucial role in most biological processes and are important targets in the development of therapeutic agents. However, small molecule drug discovery that targets PPIs remains very challenging. Targeting hot spot residues is considered the best option for inhibiting such interactions, but there are few examples of how knowledge of hot spots can be used in high throughput screening to find hit compounds. A substrate adaptor protein for a ubiquitin ligase complex, Kelch-like ECH-associated protein 1 (Keap1), negatively modulates the expression of genes involved in cellular protection against oxidative stress. Here, we focused on three arginine hot spot residues in the Keap1 substrate binding pocket (Arg380, Arg415, and Arg483), and screened the carboxylic acid library owned by Japan Tobacco Inc. for compounds that interact with the arginine residues in differential scanning fluorescence assays. Furthermore, we identified several small molecule compounds that specifically bind to the Keap1 Kelch domain hot spots by comparing binding to alanine mutant proteins (R380A, R415A, and R483A) with binding to the wild-type protein using surface plasmon resonance (SPR) screening. These compounds inhibited the protein-protein interaction between the Keap1 Kelch domain and the nuclear factor erythroid 2-related factor 2 (Nrf2) peptide, and the ubiquitination of Nrf2 catalyzed by the Cul3/RINGBox 1 E3 ligase. In addition, the binding mode of one compound (Compound 4) was determined by X-ray crystallography after validation of binding by isothermal titration calorimetry, native mass spectrometry, and nuclear magnetic resonance. Compound 4 had favorable thermodynamic properties, and noncovalently bound to Keap1 with a stoichiometry of 1:1. Our results suggest that Compound 4 could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions such as oxidative stress response, inflammation, and carcinogenesis. We believe that the use of a set of complementary biophysical techniques including the SPR assay with single alanine mutant of hot spots provides opportunities to identify hit compounds for developing inhibitors of PPIs.

Discovery of Novel NLRP3 Inflammasome Inhibitors Composed of an Oxazole Scaffold Bearing an Acylsulfamide.

The NLRP3 inflammasome plays an important role in the defense mechanism of the innate immune system and has recently attracted much attention as a drug target for various inflammatory disorders. Among the strategies for generating the novel chemotype in current drug discovery, scaffold hopping and bioisosteric replacement are known to be attractive approaches. As the results of our medicinal chemistry campaign, which involved exploration of core motifs using a ring closing approach, a five-membered oxazole-based scaffold was identified, and subsequent implementation of bioisosteric replacement led to discovery of a novel chemical class of NLRP3 inflammasome inhibitor bearing the acylsulfamide group. Further optimization of aniline and sulfamide moieties to improve potency in human whole blood assay led to the identification of the orally bioactive compound 32 in the LPS challenge model. Furthermore, compound 32 attenuated kidney injury in adriamycin-induced glomerulonephritis in mice. These investigations indicated that the NLRP3 inhibitor could be a potential therapeutic agent for glomerulonephritis.

Fragment-Based Discovery of Novel VE-PTP Inhibitors Using Orthogonal Biophysical Techniques.

Tyrosine phosphorylation is an essential post-translational modification that regulates various biological events and is implicated in many diseases including cancer and atherosclerosis. Vascular endothelial protein tyrosine phosphatase (VE-PTP), which plays an important role in vascular homeostasis and angiogenesis, is therefore an attractive drug target for these diseases. However, there are still no drugs targeting PTP including VE-PTP. In this paper, we report the discovery of a novel VE-PTP inhibitor, Cpd-2, by fragment-based screening combining various biophysical techniques. Cpd-2 is the first VE-PTP inhibitor with a weakly acidic structure and high selectivity, unlike known strongly acidic inhibitors. We believe that this compound represents a new possibility for the development of bioavailable VE-PTP inhibitors.

Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1-Nrf2 PPI Inhibitor.

Oxidative stress is one of the causes of progression of chronic kidney disease (CKD). Activation of the antioxidant protein regulator Nrf2 by inhibition of the Keap1-Nrf2 protein-protein interaction (PPI) is of interest as a potential treatment for CKD. We report the identification of the novel and weak PPI inhibitor 7 with good physical properties by a high throughput screening (HTS) campaign, followed by structural and computational analysis. The installation of only methyl and fluorine groups successfully provided the lead compound 25, which showed more than 400-fold stronger activity. Furthermore, these dramatic substituent effects can be explained by the analysis of using isothermal titration calorimetry (ITC). Thus, the resulting 25, which exhibited high oral absorption and durability, would be a CKD therapeutic agent because of the dose-dependent manner for up-regulation of the antioxidant protein heme oxigenase-1 (HO-1) in rat kidneys.

The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action.

AMP deaminase 2 (AMPD2) has been thought to play an important role in energy homeostasis and immuno-oncology, while selective AMPD2 inhibitors are highly demanded to clarify the physiological function of AMPD2. In this report, we describe selective AMPD2 inhibitors inducing allosteric modulation. Based on hypothesis that compounds that exhibit increased inhibition by preincubation would cause conformational change of the enzyme, starting from HTS hit compound 4, we discovered compound 8 through the SAR study. From X-ray structural information of 8, this chemical series has a novel mechanism of action that changes the substrate pocket to prevent AMP from binding. Further elaboration of compound 8 led to the tool compound 21 which exhibited potent inhibitory activity of AMPD2 in ex vivo evaluation of mouse liver.

Exploring the optimal reverse supply chain for e-waste treatment under Chinese government subsidy.

This study aims to analyze the influence of Chinese government subsidy on e-waste treatment formal and informal reverse supply chains (RSC) and to explore the optimal formal channel structure. Under the formal recycler-Stackelberg game, we establish three game theory models respectively under the conditions of price insensitive and price sensitive overall collection quantity. In each model, a dual-channel RSC, the green technology investment decision of formal recycler and a subsidy for formal recycler are modelled. Besides, the three models are different in collectors and collection effort implementers of the formal channel. Through mathematical modelling and comparison analysis, the study concludes that the best choice for the formal recycling enterprises is to establish its own collection channel or centralize other independent collection channels. Under the condition of price insensitive overall collection quantity, the suboptimal choice is to implement collection effort positively. Under the condition of price sensitive overall collection quantity, the suboptimal choice is to outsource the collection effort when formal recycling enterprises benefit more from the collection effort. And the phenomenon is more outstanding when the overall collection quantity can be greatly improved by the collection price. For governments, they are recommended to prudently implement the subsidy and determine the amount of subsidy because the subsidy may benefit informal channels and the effectiveness of the subsidy varies along with formal channel structures. This study is beneficial for the promotion of formal RSC by providing the optimal channel structure for formal recycling enterprises and indicating the optimal subsidy for governments.

Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors.

Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC50 values in an enzymatic assay. We also explored the C4-position of the tricyclic core to reproduce the interaction observed with the C3-position substitution, and the pyrrolidine compound showed the same level of IC50 values. By optimizing an interaction with the Asn255 sidechain through a docking simulation, compounds with 2-carboxy pyrrole moiety also showed single-digit nM IC50 values without having a cation-pi interaction with the Arg258 sidechain.

Fragment-based lead discovery to identify novel inhibitors that target the ATP binding site of pyruvate dehydrogenase kinases.

A fragment-based lead discovery approach was applied to Pyruvate Dehydrogenase Kinases (PDHKs) to discover inhibitors against the ATP binding site with novel chemotypes. X-ray fragment screening toward PDHK4 provided a fragment hit 1 with a characteristic interaction in a deep pocket of the ATP binding site. While known inhibitors utilize several water molecules in a deep pocket to form water-mediated hydrogen bond interactions, the fragment hit binds deeper in the pocket with a hydrophobic group. Displacement of a remaining water molecule in the pocket led to the identification of lead compound 7 with a notable improvement in inhibition potency. This lead compound possessed high ligand efficiency (LE) and showed decent selectivity profile. Two additional lead compounds 10 and 13 with new scaffolds with tricyclic and bicyclic cores were generated by merging structural information of another fragment hit 2. The characteristic interaction of these novel inhibitors in a deep pocket provides new structural insights about PDHKs ATP binding site and opens a novel direction for the development of PDHKs inhibitors.

Discovery of Selective Transforming Growth Factor ß Type II Receptor Inhibitors as Antifibrosis Agents.

Historically, modulation of transforming growth factor ß (TGF-ß) signaling has been deemed a rational strategy to treat many disorders, though few successful examples have been reported to date. This difficulty could be partially attributed to the challenges of achieving good specificity over many closely related enzymes that are implicated in distinct phenotypes in organ development and in tissue homeostasis. Recently, fresolimumab and disitertide, two peptidic TGF-ß blockers, demonstrated significant therapeutic effects toward human skin fibrosis. Therefore, the selective blockage of TGF-ß signaling assures a viable treatment option for fibrotic skin disorders such as systemic sclerosis (SSc). In this report, we disclose selective TGF-ß type II receptor (TGF-ßRII) inhibitors that exhibited high functional selectivity in cell-based assays. The representative compound 29 attenuated collagen type I alpha 1 chain (COL1A1) expression in a mouse fibrosis model, which suggests that selective inhibition of TGF-ßRII-dependent signaling could be a new treatment for fibrotic disorders.

Speeding drug discovery targeting RNAs: An iterative "RNA selection-compounds screening cycle" for exploring RNA-small molecule pairs.

RNA is an emerging target of next-generation drug development. Recently, new small molecules targeting RNAs were discovered by several pharmaceutical companies. Methods have been reported to identify small molecules targeting a specific RNA sequence and structural motif, however, because of diverse sequence and structural motifs potentially present in the druggable functional RNAs, large sets of structure-activity relationships (SARs) information of small molecule - RNA interactions will be required for the acceleration and efficient startup of the discovery programs toward unprecedented RNA targets. Here we describe our iterative RNA selection and compounds screening to accumulate rich information about small molecules - RNA interaction. The RNAs that selectively bind to the initial molecular target, compound 1 from our in-house chemical library (JT-library), was isolated using in vitro selection technique from a hairpin-structured RNA library mimicking precursor microRNA (pre-miRNA). Then, we engineered pre-let-7f-2 to create its mutant that can bind to compound 1 by embedding the in vitro selected RNA motif for compound 1 in the hairpin loop region. The obtained mutant pre-let-7f-2-loop-mt was used as a target for screening 316 analogs of compound 1. A surface plasmon resonance (SPR) -based screening was performed against pre-let-7f-2-loop-mt-immobilized sensor surface and we obtained four compounds that can bind to the RNA. Among these four compounds, three compounds showed higher affinity to pre-let-7f-2-loop-mt than the parental compound 1, which suggests the feasibility of our strategy for gathering the SAR information on small molecule - RNA interactions. We demonstrated only one cycle of RNA selection and compounds screening in the present study, but can continue this cycle with the selected molecule to gain new RNAs and even new RNA motifs and gather much SAR information with improved accuracy.

Discovery of a Janus Kinase Inhibitor Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052 (Delgocitinib) as a New Dermatological Agent to Treat Inflammatory Skin Disorders.

Dermatologic disorders such as atopic dermatitis arise from genetic and environmental causes and are complex and multifactorial in nature. Among possible risk factors, aberrant immunological reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clinical settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochemical properties and antidermatitis efficacy in the animal models. One of these compounds, JTE-052 (ent-60), also known as delgocitinib, has been shown to be effective and well-tolerated in human clinical trials and has recently been approved in Japan for the treatment of atopic dermatitis as the first drug among Janus kinase inhibitors.

Formalisation of informal collectors under a dual-recycling channel: A game theoretic approach.

Formalisation of informal collectors is beneficial for economical, environmental and social sustainability. Through dividing collectors and recyclers, a benchmark model consists of competitive dual formal and informal channels is established to quantitatively analyse the possibility of formalising informal collectors and study the formalisation extent. This study comprehensively compares the effects of respective subsidy or punishment targeting at collectors or recyclers in the extended policy model. The subsidy delay used to represent the response speed of the subsidy system is first included. This study indicates the influences of different factors on formalisation activity, including bargaining power, reluctance of informal collectors and recycling cost of formal channels. The policy model concluded that the subsidy on informal collectors or formal recyclers (punishment on informal collectors or informal recyclers) presents no difference regarding the formalisation extent. Based on numerical data, we studied the formalisation extent for the context of China and visualised the effects of different policies. The decremental effect of subsidy and the incremental effect of punishment are concluded in a formalisation activity. This study fills the gap of a quantitative study on formalisation activity and the results will comprehend the promotion of the formalisation of informal collectors.

Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold.

Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.