Design and Synthesis of Small Molecular probes for CNS and Kidney Disorders

The G protein regulated inwardly rectifying potassium channels (GIRK) are a family of inwardly rectifying potassium channels and are key effectors in signaling pathways. GIRK 1/2 channel subunit, predominantly found in the brain, is involved pathophysiology of various neurological disorders including, but not limited to, epilepsy, anxiety, Parkinson\u27s, pain, reward, and addiction. Previously, our laboratory had identified a series of urea containing molecules as GIRK1/2 preferring activators. Unfortunately, the urea series suffers from significant PK liabilities (solubility, brain penetration and high clearance). The chapter 1 of the dissertation describes our efforts in developing three new series of activators with improved pharmacokinetics properties while retaining activity. Human Mas-related G protein-coupled receptor X1 (MRGX1) is a part of the larger GPCR family of receptors and has restricted expression in nociceptors within the peripheral nervous system. Allosteric activation of Mrgx1 inhibits the high voltage acting Ca2+ (HVA) channel necessary for nociception. This makes it a promising target for non-addictive pain therapy. Previous efforts in our lab for optimization of hits obtained from high-throughput screening (HTS) had led to the development of a selective MrgX1 allosteric agonist, ML382. Chapter-2 shows our SAR studies around ML382 to overcome potential pharmacokinetic liabilities of ML382 and identify newer and more potent MrgX1 allosteric agonists. Through our medicinal chemistry based efforts we were able to identify 10 fold more potent agonists compared to ML382. Progressive chronic kidney disease (CKD) is characterized by a total or considerable loss in kidney function, affects approximately 1 in 10 people around the world. Previous work in our collaborator\u27s laboratory has established the role of the transient receptor potential canonical-5 (TRPC5) ion channel in mediating calcium influx in podocyte leading to cytoskeletal changes and loss of functionality. Chapter-3 describes our medicinal chemistry based approach for the design, synthesis and characterization of novel benzimidazole basedTRPC5 inhibitors We were able to bring the activity from micro-molar to low nano molar

Characterization of Basin-Scale Dynamic Storage–Discharge Relationship Using Daily GRACE Based Storage Anomaly Data

Despite the fact that streamflow occurs mainly due to depletion of storage, our knowledge on how a drainage basin stores and releases water is very limited due to measurement limitations. A window of opportunity, however, is provided to us by GRACE (Gravity Recovery and Climate Experiment) satellite mission that provides storage anomaly (San) data. Many studies have explored a range of potential applications of San data such as flood forecasting. Here we argue that the capability of GRACE satellite mission has not been fully explored as most of the studies in the past have performed analysis using monthly San data for large river basins. In this study, we use daily San data for several mid-sized catchments to perform storage–discharge analysis. Our results support the earlier notion that storage–discharge relationship is highly dynamic. Furthermore, we demonstrate that San data can be exploited for prediction of k of the Brutsaet–Nieber equation −dQ/dt = kQα (Q is discharge at time t). For comparison we also use storage information provided by Catchment Land Surface Model (CLSM) as well as past discharge information to predict k. Our results suggest that GRACE based storage information can be used to predict k reasonably well in gauged as well as ungauged basins. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Integration of a proton exchange membrane fuel cell system for voltage and frequency stabilization in a micro hydro system

This work discusses the frequency and voltage stabilization in a stand-alone self-excited induction generator system (SEIGs) using a fuel cell (FC)-based generation unit. The proposed SEIG acts as the power generator in a microhydro system. Variations in load create fluctuations in voltage and frequency, which have to be stabilized. In this work, authors have proposed integrating a FC-based generation unit with the existing SEIGs to improve its voltage and frequency profiles. For this work, a proton exchange membrane fuel cell (PEMFC) has been considered. Modeling of a 36 kW PEMFC is taken for the proposed work, which has to be integrated with the 22 kW self-excited induction generator. The design of the system and converter parameters have also been included in the work. Authors have proposed an orthogonal current component-based controlstructure that provides independent control of active and reactive power in the system. Considering the FC system working conditions, this article aims to assure optimum power transfer capability between the self-excited induction generator, fuel cell system, and the time-varying loads. The system is exposed to time-varying RL loads dynamic load switching, and the performance is evaluated in real-time. OP 4510 real-time simulator verifies the proposed system's dynamic model created using Matlab/Simulink

Evaluation of an instantaneous dryness index-based calibration-free continuous hydrological model in India

Traditional continuous hydrological models have a large number of free parameters whose values need to be determined through calibration, and thus their applicability is limited to gauged basins. For prediction in ungauged catchments, hydrologists generally follow regionalization methods to develop region-specific calibration-free continuous models. An alternative attempt was made recently to develop a calibration-free model by proposing an empirically derived universal ‘decay function’ that enables definition of instantaneous dryness index as a function of antecedent rainfall and solar energy. The model was earlier tested in the US, and its performance was found to be comparable to that shown by regionalization-based models. Here, we test the instantaneous dryness index-based calibration-free model considering data from 108 Indian catchments. The medians of coefficient of determination (R2), Nash–Sutcliffe efficiency (NSE) and Kling–Gupta efficiency (KGE) values for the study catchments, respectively, are 0.50, 0.38 and 0.40. Furthermore, the model's performance significantly improved upon Box–Cox transformation (RBC2, NSEBC and KGEBC, respectively, are 0.70, 0.52 and 0.57), suggesting that the model predicts discharge quite well except during flood periods. Overall, our results suggest the model can be used as an alternative platform for predicting discharge in ungauged catchments in the US and peninsular India, if not in every part of the world

Evaluation of super-twisting SMC and NSC combination for power control in multi-source renewable power generation system

This work is based on the evaluation of a super-twisting sliding mode controller for power control in an isolated multi-source renewable generation system. The hybrid multi-source system taken into consideration, in this case, is made up of three different generation units. The main generation unit is a 22kW micro-hydro system with a self-excited induction generator. To this, a 7.5kW doubly fed induction generator-based wind energy conversion system is integrated. An 18kW solar PV system connected to a battery energy storage system is connected at the dc-link. All the above systems are integrated through a bidirectional nine-switch converter. The autonomous hybrid system's power control is solely done by the nine-switch converter. In this work, efforts have been made to combine the robustness and accuracy of super-twisting sliding mode controllers with the reliability and flexibility of the nine-switch converters. The performance evaluation of the above combination is done with various load and source side disturbances. The system's uninterrupted power supply capability has also been examined in this work. Using the MATLAB environment, the system's performance is evaluated, examined, and the same has been verified using an OPAL-RT 4510 real-time simulator

Further synthesis and biological characterization of a series of 2-sulfonamidebenzamides as allosteric modulators of MrgX1

The present study describes our continued efforts in the discovery and characterization of a series of 2-sulfonamidebenzamides as allosteric modulators of MrgX1. MrgX1 has been shown to be an attractive target as a non-opioid receptor for the potential treatment of chronic pain. Working from our original compound, ML382, and utilizing iterative medicinal chemistry, we have identified key halogen substituents that improve MrgX1 potency by ~8-fold. In addition, we have evaluated the compounds in Tier 1 DMPK assays and have identified key compounds that impart improved potency and microsomal stability

PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells

Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy

ZRC3308 Monoclonal Antibody Cocktail Shows Protective Efficacy in Syrian Hamsters against SARS-CoV-2 Infection

We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZRC3308-B10 in the ratio 1:1 for COVID-19 treatment. The mAbs were designed to have reduced immune effector functions and increased circulation half-life. mAbs showed good binding affinities to non-competing epitopes on RBD of SARS-CoV-2 spike protein and were found neutralizing SARS-CoV-2 variants B.1, B.1.1.7, B.1.351, B.1.617.2, and B.1.617.2 AY.1 in vitro. The mAb cocktail demonstrated effective prophylactic and therapeutic activity against SARS-CoV-2 infection in Syrian hamsters. The antibody cocktail appears to be a promising candidate for prophylactic use and for therapy in early COVID-19 cases that have not progressed to severe disease