Human DNA ligases: a comprehensive new look for cancer therapy.

Living organisms belonging to all three domains of life, viz., eubacteria, archaeabacteria, and eukaryotes encode one or more DNA ligases. DNA ligases are indispensable in various DNA repair and replication processes and a deficiency or an inhibition of their activity can lead to accumulation of DNA damage and strand breaks. DNA damage, specially strand breaks at unsustainable levels can lead to replication block and/or cell death. DNA ligases as potential anticancer targets have been realized only recently. There is enough rationale to suggest that ligases have a tremendous potential for novel therapeutics including anticancer and antibacterial therapy, specially when the world is facing acute problems of drug resistance and chemotherapy failure, with an immediate need for new therapeutic targets. Here, we review the current state of the art in the development of human ligase inhibitors, their structures, molecular mechanisms, physiological effects, and their potential in future cancer therapy. Citing examples, we focus on strategies for improving the activity and specificity of existing and novel inhibitors by using structure-based rational approaches. In the end, we describe potential new sites on the ligase I protein that can be targeted for the development of novel inhibitors. This is the first comprehensive review to compile all known human ligase inhibitors and to provide a rationale for the further development of ligase inhibitors for cancer therapy.

Pharmacophore-based screening and identification of novel human ligase I inhibitors with potential anticancer activity.

Human DNA ligases are enzymes that are indispensable for DNA replication and repair processes. Among the three human ligases, ligase I is attributed to the ligation of thousands of Okazaki fragments that are formed during lagging strand synthesis during DNA replication. Blocking ligation therefore can lead to the accumulation of thousands of single strands and subsequently double strand breaks in the DNA, which is lethal for the cells. The reports of the high expression level of ligase I protein in several cancer cells (versus the low ligase expression level and the low rate of division of most normal cells in the adult body) support the belief that ligase I inhibitors can target cancer cells specifically with minimum side effects to normal cells. Recent publications showing exciting data for a ligase IV inhibitor exhibiting antitumor activity in mouse models also strengthens the argument for ligases as valid antitumor targets. Keeping this in view, we performed a pharmacophore-based screening for potential ligase inhibitors in the Maybridge small molecule library and procured some of the top-ranking compounds for enzyme-based and cell-based in vitro screening. We report here the identification of novel ligase I inhibitors with potential anticancer activity against a colon cancer cell line.

Thermal, Electrical, and Environmental Safeties of Sulfide Electrolyte-Based All-Solid-State Li-Ion Batteries.

The next generation of all-solid-state lithium-ion batteries (ASLIBs) based on solid-state sulfide electrolytes (SSEs) is closest to commercialization. Understanding the overall safety behavior of SSE-ASLIBs is necessary for their product design and commercialization. However, their safety behavior in real-life situations, such as battery exposure to high temperature, overcharge, mechanical rupture, and air exposure, remains largely unknown. Herein, we report preliminary but needed evidence of (i) significantly improved resistance to electrical shorting at high temperatures, (ii) reduced heat generation when subjected to excessive heat, (iii) tolerable harmful gas generation when subjected to air exposure followed by high-temperature heating, and (iv) high-voltage charge stability when a battery is overcharged (5.5 V charge) in SSE-based ASLIBs compared to commercial liquid electrolyte-based LIBs (LE-LIBs). Furthermore, the result shows that SSEs can self-induce a fast and effective battery shut-down capability in ASLIBs and avoid thermal runaway upon mechanical damage and exposure to air.

Enhancing Electrochemical Performances of Rechargeable Lithium-Ion Batteries via Cathode Interfacial Engineering.

Lithium-ion batteries (LIBs) have transformed modern electronics and rapidly advancing electric vehicles (EVs) due to their high energy and power densities, cycle-life, and acceptable safety. However, the comprehensive commercialization of EVs necessitates the invention of LIBs with much enhanced and stable electrochemical performances, including higher energy/power density, cycle-life, and operational safety, but at a lower cost. Herein, we report a simple method for improving the high-voltage (up to 4.5 V) charge capability of LIBs by applying a Li+-ion-conducting artificial cathode-electrolyte interface (Li+-ACEI) on the state-of-the-art cathode, LiCoO2 (LCO). A superionic ceramic single Li+ ion conductor, lithium aluminum germanium phosphate (Li1.5Al0.5Ge1.5(PO4)3, LAGP), has been used as a novel Li+-ACEI. The application of Li+-ACEI on LCO involves a scalable and straightforward wet chemical process (sol-gel method). Cycling performance, including high voltage charge, of bare and LAGP-coated cathodes has been determined against the most energy-dense anode (lithium, Li metal) and state-of-the-art carbonate-based organic liquid electrolyte (OLE). The application of an LAGP-based Li+-ACEI on LCO displays many improvements: (i) reduced charge-transfer and interfacial resistance; (ii) higher discharge capacity (167.5 vs 155 mAh/g) at 0.2C; (iii) higher Coulombic efficiency (98.9 vs 97.8%) over 100 cycles; and (iv) higher rate capability (143 vs 80.1 mAh/g) at 4C. Structural and morphological characterizations have substantiated the improved electrochemical behavior of bare and Li+-ACEI LCO cathodes against the Li anode.

Self-powered, ultrasensitive, room temperature humidity sensors using SnS2 nanofilms.

Humidity monitoring has become extremely vital in various technological fields such as environment control, biomedical engineering, and so on. Therefore, a substantial interest lies in the development of fast and highly sensitive devices with high figures of merit. Self-powered and ultrasensitive humidity sensors based on SnS2 nanofilms of different film thicknesses have been demonstrated in this work. The sensing behavior has been investigated in the relative humidity (RH) range of 2-99%. The observed results reveal a remarkable response and ultrafast detection even with zero applied bias (self-powered mode), with response and recovery times of ~ 10 and ~ 0.7 s, respectively. The self-powered behavior has been attributed to the inhomogeneities and the asymmetry in the contact electrodes. The highest sensitivity of ~ 5.64 × 106% can be achieved at an applied bias of 5 V. This approach of fabricating such highly responsive, self-powered and ultrafast sensors with simple device architectures will be useful for designing futuristic sensing devices.

Self-Powered, Broad Band, and Ultrafast InGaN-Based Photodetector.

A self-powered, broad band and ultrafast photodetector based on n+-InGaN/AlN/n-Si(111) heterostructure is demonstrated. Si-doped (n+ type) InGaN epilayer was grown by plasma-assisted molecular beam epitaxy on a 100 nm thick AlN template on an n-type Si(111) substrate. The n+-InGaN/AlN/n-Si(111) devices exhibit excellent self-powered photoresponse under UV-visible (300-800 nm) light illumination. The maximum response of this self-powered photodetector is observed at 580 nm for low-intensity irradiance (0.1 mW/cm2), owing to the deep donor states present near the InGaN/AlN interface. It shows a responsivity of 9.64 A/W with rise and fall times of 19.9 and 21.4 µs, respectively. A relation between the open circuit voltage and the responsivity has been realized.

Multiple Machine Learning Based-Chemoinformatics Models for Identification of Histone Acetyl Transferase Inhibitors.

The histone acetyl transferase (HAT) are involved in acetylation of histones that lead to transcription activation in numerous gene regulatory mechanisms. There are very few GCN5 HAT inhibitors reported despite of their role in cancer progression. In this study, we have utilized in-silico virtual screening approaches based on various machine learning algorithm to identify potent inhibitors of GCN5 HAT from commercially available Maybridge library. We have generated predictive chemoinformatics models based on k-Nearest neighbour, naïve Bayesian, Random Forest and Support Vector Machine. Based on statistical parameters, the RF and SVM models have shown comparative performance. Therefore, we performed the virtual screening with these two models and the consensus hits were selected for further evaluation using molecular docking into the active site of GCN-5 HAT. Finally, a set of 10 molecules were selected and subjected to biological evaluation. Subsequently, inhibition of acetylation shown by three out of the ten molecules in the in-vitro experiments validated their utility as potential HAT inhibitors. Furthermore, the selected hits have also shown weak cell growth decrease in MCF-7 cancer cell lines, which suggests that after subsequent structural optimization the identified molecules may further be explored for the development of anti-cancer agents.

Identification of human flap endonuclease 1 (FEN1) inhibitors using a machine learning based consensus virtual screening.

Human Flap endonuclease1 (FEN1) is an enzyme that is indispensable for DNA replication and repair processes and inhibition of its Flap cleavage activity results in increased cellular sensitivity to DNA damaging agents (cisplatin, temozolomide, MMS, etc.), with the potential to improve cancer prognosis. Reports of the high expression levels of FEN1 in several cancer cells support the idea that FEN1 inhibitors may target cancer cells with minimum side effects to normal cells. In this study, we used large publicly available, high-throughput screening data of small molecule compounds targeted against FEN1. Two machine learning algorithms, Support Vector Machine (SVM) and Random Forest (RF), were utilized to generate four classification models from huge PubChem bioassay data containing probable FEN1 inhibitors and non-inhibitors. We also investigated the influence of randomly selected Zinc-database compounds as negative data on the outcome of classification modelling. The results show that the SVM model with inactive compounds was superior to RF with Matthews's correlation coefficient (MCC) of 0.67 for the test set. A Maybridge database containing approximately 53 000 compounds was screened and top ranking 5 compounds were selected for enzyme and cell-based in vitro screening. The compound JFD00950 was identified as a novel FEN1 inhibitor with in vitro inhibition of flap cleavage activity as well as cytotoxic activity against a colon cancer cell line, DLD-1.

A Novel Benzocoumarin-Stilbene Hybrid as a DNA ligase I inhibitor with in vitro and in vivo anti-tumor activity in breast cancer models.

Existing cancer therapies are often associated with drug resistance and toxicity, which results in poor prognosis and recurrence of cancer. This necessitates the identification and development of novel therapeutics against existing as well as novel cellular targets. In this study, a novel class of Benzocoumarin-Stilbene hybrid molecules were synthesized and evaluated for their antiproliferative activity against various cancer cell lines followed by in vivo antitumor activity in a mouse model of cancer. The most promising molecule among the series, i.e. compound (E)-4-(3,5-dimethoxystyryl)-2H-benzo[h]chromen-2-one (19) showed maximum antiproliferative activity in breast cancer cell lines (MDA-MB-231 and 4T1) and decreased the tumor size in the in-vivo 4T1 cell-induced orthotopic syngeneic mouse breast cancer model. The mechanistic studies of compound 19 by various biochemical, cell biology and biophysical approaches suggest that the compound binds to and inhibits the human DNA ligase I enzyme activity that might be the cause for significant reduction in tumor growth and may constitute a promising next-generation therapy against breast cancers.

Dynamics of replication proteins during lagging strand synthesis: A crossroads for genomic instability and cancer.

DNA replication is a complex phenomenon that requires the concerted action of several enzymes, together with their protein and non-protein cofactors. In the nucleus, the two DNA strands are duplicated by two completely independent methods due to their anti-parallel orientation and the restrictive nature of DNA polymerases that allow DNA synthesis in the 5'-3' direction only. In this review, we focus on the proteins that are involved in the more complex and discontinuous process of lagging strand DNA synthesis by the formation of small DNA fragments called Okazaki fragments which are later sealed to form a continuous strand of DNA. We try and connect all the protein-protein interactions important for lagging strand synthesis in the S-phase of the cell cycle, describe the dynamics of these interactions and go on to discuss the post-translational modifications that affect them. We also look at how mutations in any of the players of the lagging strand synthesis can cause genomic instability leading to cancer and discuss if any of the players may be targeted for cancer therapy.

Discovery of 3-Arylcoumarin-tetracyclic Tacrine Hybrids as Multifunctional Agents against Parkinson's Disease.

A series of multifunctional directed 3-arylcoumarin-tetracyclic tacrine derivatives was designed and synthesized for the treatment of Parkinson's disease (PD). A number of derivatives (18, 19, 20, 21, and 24) demonstrated significant reduction of aggregation of "human" alpha-synuclein (α-synuclein) protein, expressing on transgenic Caenorhabditis elegans (C. elegans) model NL5901. Moreover, compounds 16, 18, and 24 also exhibited good antioxidant properties and significantly increased the dopamine (DA) content in N2 and NL5901 strains of C. elegans. Interestingly, the protective efficacy of these hybrids seems to be mediated via activation of longevity promoting transcription factor DAF-16. In addition, molecular modeling studies have evidenced the exquisite interaction of most active compounds 18 and 24 with α-synuclein protein. Taken together, the data indicate that the derivatives may be useful leads against aging and age associated PD.