Repurposing Tranexamic Acid as an Anticancer Agent

Tranexamic Acid (TA) is a clinically used antifibrinolytic agent that acts as a Lys mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic Lys and Arg, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. Further, TA inhibited uptake of Lys and Arg by cancer cells. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

A medicinal chemist’s perspective towards structure activity relationship of heterocycle based anti-cancer agents

Aim: To describe structure activity relationship of heterocyclic derivatives with multi-targeted anticancer activity. Objectives: With the following goals in mind, this review tries to describe significant recent advances in the medicinal chemistry of heterocycle-based compounds: (1) To shed light on recent literature focused on heterocyclic derivatives' anticancer potential; (2) To discuss recent advances in the medicinal chemistry of heterocyclic derivatives, as well as their biological implications for cancer eradication; (3) To summarise the comprehensive correlation of structure activity relationship (SAR) with pharmacological outcomes in cancer therapy. Background: Cancer remains one of the major serious health issues devastating the world today. Cancer is a complex disease in which improperly altered cells proliferate at an uncontrolled, rapid, and severe rate. Variables such as poor dietary habits, high stress, age, and smoking, can all contribute to the development of cancer. Cancer can affect almost any organ or tissue, although the brain, breast, liver, and colon are the most frequently affected organs. From several years, surgical operations and irradiation are in use along with chemotherapy as a primary treatment of cancer but still effective treatment of cancer remains a huge challenge. Chemotherapy is now one of the most effective strategies to eradicate cancer, although it has been shown to have a number of cytotoxic and unfavourable effects on normal cells. Despite all of these cancer treatments, there are several other targets for anticancer drugs. Cancer can be effectively eradicated by focusing on these targets, which include both cell-specific and receptor-specific targets such as tyrosine kinase receptors (TKIs). Heterocyclic scaffolds also have a variety of applications in drug development and are a common moiety in the pharmaceutical, agrochemical, and textile industries. Methods: The association between structural activity relationship data of many powerful compounds and their anticancer potential in vitro and in vivo has been studied. SAR of powerful heterocyclic compounds can also be generated using molecular docking simulations, as reported vastly in literature. Conclusions: Heterocycles have a wide range of applications, from natural compounds to synthesised derivatives with powerful anticancer properties. To avoid cytotoxicity or unfavourable effects on normal mammalian cells due to a lack of selectivity towards the target site, as well as to reduce the occurrence of drug resistance, safer anticancer lead compounds with higher potency and lower cytotoxicity are needed. This review emphasizes on design and development of heterocyclic lead compounds with promising anticancer potential.

Structure-Based In Silico Investigation of Agonists for Proteins Involved in Breast Cancer

Cancer is recognized as one of the main causes of mortality worldwide by the World Health Organization. The high cost of currently available cancer therapy and certain limitations of current treatment make it necessary to search for novel, cost-effective, and efficient methods of cancer treatment. Therefore, in the current investigation, sixty-two compounds from five medicinal plants (Tinospora cordifolia, Ocimum tenuiflorum, Podophyllum hexandrum, Andrographis paniculata, and Beta vulgaris) and two proteins that are associated with breast cancer, i.e., HER4/ErbB4 kinase and ERα were selected. Selected compounds were screened using Lipinski’s rule, which resulted in eighteen molecules being ruled out. The remaining forty-four compounds were then taken forward for docking studies followed by molecular dynamics studies of the best screened complexes. Results showed that isocolumbin, isopropylideneandrographolide, and 14-acetylandrographolide were potential lead compounds against the selected breast cancer receptors. Furthermore, in vitro studies are required to confirm the efficacy of the lead compounds.

A Review on Parallel Virtual Screening Softwares for High-Performance Computers

Drug discovery is the most expensive, time-demanding, and challenging project in biopharmaceutical companies which aims at the identification and optimization of lead compounds from large-sized chemical libraries. The lead compounds should have high-affinity binding and specificity for a target associated with a disease, and, in addition, they should have favorable pharmacodynamic and pharmacokinetic properties (grouped as ADMET properties). Overall, drug discovery is a multivariable optimization and can be carried out in supercomputers using a reliable scoring function which is a measure of binding affinity or inhibition potential of the drug-like compound. The major problem is that the number of compounds in the chemical spaces is huge, making the computational drug discovery very demanding. However, it is cheaper and less time-consuming when compared to experimental high-throughput screening. As the problem is to find the most stable (global) minima for numerous protein–ligand complexes (on the order of 106 to 1012), the parallel implementation of in silico virtual screening can be exploited to ensure drug discovery in affordable time. In this review, we discuss such implementations of parallelization algorithms in virtual screening programs. The nature of different scoring functions and search algorithms are discussed, together with a performance analysis of several docking softwares ported on high-performance computing architectures.

Modern Paradigm Towards Potential Target Identification for Antiviral (SARS-nCoV-2) and Anticancer Lipopeptides: A Pharmacophore-Based Approach

Background: Lipopeptides are potential microbial metabolites that are abandoned with broad spectrum biopharmaceutical properties ranging from antimicrobial, antiviral and anticancer, etc. Clinical studies are not much explored beyond the experimental methods to understand drug mechanisms on target proteins at the molecular level for large molecules. Due to the less available studies on potential target proteins of lipopeptide based drugs, their potential inhibitory role for more obvious treatment on disease have not been explored in the direction of lead optimization. However, Computational approaches need to be utilized to explore drug discovery aspects on lipopeptide based drugs, which are time saving and cost-effective techniques. Methods: Here a ligand-based drug discovery approach is coupled with reverse pharmacophore-mapping for the prediction of potential targets for antiviral (SARS-nCoV-2) and anticancer lipopeptides. Web-based servers PharmMapper and Swiss Target Prediction are used for the identification of target proteins for lipopeptides surfactin and iturin produced by Bacillus subtilis. Results: The studies have given the insight to treat the diseases with next-generation large molecule therapeutics. Results also indicate the affinity for Angiotensin-Converting Enzymes (ACE) and proteases as the potential viral targets for these categories of peptide therapeutics. A target protein for the Human Papilloma Virus (HPV) has also been mapped. Conclusion: The work will further help in exploring computer-aided drug designing of novel compounds with greater efficiency where the structure of the target proteins and lead compounds are known.

Ethnic Use, Phytochemistry, and Pharmacology of Cyperus rotundus

Cyperus rotundus (nut grass in English) is a perennial erect sedge plant and is distributed in over 90 countries of the world, where it has been mostly classified as a highly invasive weed. Despite this classification, the plant has been considered from traditional times to be medicinally important. The traditional uses of the plant in various countries include uses against various gastrointestinal tract disorders, skin diseases, leprosy, fever, and neurological disorders. Evaluation of the plant and especially its rhizomes in a scientific manner has revealed the presence of numerous phytochemicals and wide-ranging pharmacological activities, which include anti-microbial, gastrointestinal, wound healing, anti-diabetic, anti-cancer, anti-malarial, anti-obesity, hepatoprotective, and anti-pyretic activity. The scientific validation of a number of traditional uses strongly indicates that the plant may prove useful in the discovery of a number of lead compounds and novel drugs.

Isolation of Antimalarial Agents From Indonesian Medicinal Plants: Swietenia mahagoni and Pluchea indica

Malaria is a neglected tropical disease that still demands serious efforts to tackle successfully, including the need for new antimalarial lead compounds to combat drug-resistant Plasmodium. Intensive phytochemical and pharmacological investigation into the Indonesian medicinal plants Swietenia mahagoni and Pluchea indica successfully revealed 5 constituents. Antimalarial bioassays indicated 34,5-tri- O-caffeoylquinic acid (4) to be the most active against Plasmodium falciparum 3D7 and Dd2 strains with IC50 values of 8.2 and 8.8 µM, respectively. No cytotoxicity was observed against Human Embryonic Kidney cells at a concentration of 40 µM.

Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?

Cancer has become a global health problem, accounting for one out of six deaths. Despite the recent advances in cancer therapy, there is still an ever-growing need for readily accessible new therapies. The process of drug discovery and development is arduous and takes many years, and while it is ongoing, the time for the current lead compounds to reach clinical trial phase is very long. Drug repurposing has recently gained significant attention as it expedites the process of discovering new entities for anticancer therapy. One such potential candidate is the antimalarial drug, artemisinin that has shown anticancer activities in vitro and in vivo. In this review, major molecular and cellular mechanisms underlying the anticancer effect of artemisinin and its derivatives are summarised. Furthermore, major mechanisms of action and some key signaling pathways of this group of compounds have been reviewed to explore potential targets that contribute to the proliferation and metastasis of tumor cells. Despite its established profile in malaria treatment, pharmacokinetic properties, anticancer potency, and current formulations that hinder the clinical translation of artemisinin as an anticancer agent, have been discussed. Finally, potential solutions or new strategies are identified to overcome the bottlenecks in repurposing artemisinin-type compounds as anticancer drugs.