Many methods have been developed to capture the biological similarity between two compounds for use in drug discovery. A variety of similarity metrics have been introduced, the Tanimoto coefficient being the most prominent. Many of the approaches assume that molecular features or descriptors that do not relate to the biological activity carry the same weight as the important aspects in terms of biological similarity. Herein, a novel similarity searching approach using a Bayesian inference network is discussed. Similarity searching is regarded as an inference or evidential reasoning process in which the probability that a given compound has biological similarity with the query is estimated and used as evidence. Our experiments demonstrate that the similarity approach based on Bayesian inference networks is likely to outperform the Tanimoto similarity search and offer a promising alternative to existing similarity search approaches.
Several modern treatment strategies have been adopted to combat cancer with the aim of minimizing toxicity. Medicinal plant-based compounds with the potential to treat cancer have been widely studied in preclinical research and have elicited many innovations in cutting-edge clinical research. In parallel, researchers have eagerly tried to decrease the toxicity of current chemotherapeutic agents either by combining them with herbals or in using herbals alone. The aim of this article is to present an update of medicinal plants and their bioactive compounds, or mere changes in the bioactive compounds, along with herbal edibles, which display efficacy against diverse cancer cells and in anticancer therapy. It describes the basic mechanism(s) of action of phytochemicals used either alone or in combination therapy with other phytochemicals or herbal edibles. This review also highlights the remarkable synergistic effects that arise between certain herbals and chemotherapeutic agents used in oncology. The anticancer phytochemicals used in clinical research are also described; furthermore, we discuss our own experience related to semisynthetic derivatives, which are developed based on phytochemicals. Overall, this compilation is intended to facilitate research and development projects on phytopharmaceuticals for successful anticancer drug discovery.
Xanthine oxidase (XO) is the enzyme responsible for the catabolism of purines and their conversion into uric acid. XO is thus the target for the treatment of hyperuricemia and gout. For more than 50 years the only XO inhibitor drug available on the market was the purine analogue allopurinol. In the last decade there has been a resurgence in the search for new inhibitors of XO, as the activity of XO and hyperuricemia have also been associated with a variety of conditions such as diabetes, hypertension, and other cardiovascular diseases. In recent years the non-purine inhibitor febuxostat was approved in Europe and the USA for the treatment of hyperuricemia. This drug was followed by another XO inhibitor called topiroxostat. This review discusses the molecular structures and activities of the multiple classes of inhibitors that have been developed since the discovery of allopurinol, with a brief review of the molecular interactions between inhibitors and XO active site residues for the most important molecules. The challenges ahead for the discovery of new inhibitors of XO with novel chemical structures are discussed.
Benzimidazole is a heterocyclic ring system that has been widely studied in the pharmaceutical field. For the past decade, numerous benzimidazole derivatives have been synthesized and evaluated for their wide range of pharmacological activities, which are beneficial for drug development. This article presents the biological effects of benzimidazole derivatives in each invention from 2015 to 2020. Two patent databases, Google Patents and Lens, were used to locate relevant granted patent applications. Specifically, this review delineates the role of patented benzimidazoles from a disease-centric perspective and examines the mechanisms of action of these compounds in related diseases. Most of the benzimidazoles have shown good activities against various target proteins. Whilst several of them have progressed into clinical trials, most patents presented novel therapeutic approaches for respective target diseases. Hence, their potential in being developed into clinical drugs are also discussed.
The benzoxazole moiety is widely found in various natural compounds, which are often found to be biologically active. Due to its versatile biological properties, benzoxazole has been incorporated as an essential pharmacophore and substructure in many medicinal compounds. In the past years, numerous benzoxazole derivatives have been synthesised and evaluated for their biological potential. The wide range in therapeutic potential of benzoxazole derivatives is related to the favourable interactions of the benzoxazole moiety with different protein targets. Herein we review the biological activities of benzoxazole derivatives patented within the past six years. Using the Lens database, granted patents issued from 2015 to 2020 were retrieved. The patented benzoxazole derivatives demonstrated excellent activity against various protein targets and diseases, with some reaching clinical trial stage. Pharmacological and medicinal aspects of patented benzoxazole derivatives are discussed. The recent development and drawbacks are also reviewed.
Dihydrofolate reductase (DHFR) is a key enzyme involved in the folate pathway that has been heavily targeted for the development of therapeutics against cancer and bacterial and protozoa infections amongst others. Despite being an essential enzyme for Mycobacterium tuberculosis (Mtb) viability, DHFR remains an underexploited target for tuberculosis (TB) treatment. Herein, we report the preparation and evaluation of a series of compounds against Mtb DHFR (MtbDHFR). The compounds have been designed using a merging strategy of traditional pyrimidine-based antifolates with a previously discovered unique fragment hit against MtbDHFR. In this series, four compounds displayed a high affinity against MtbDHFR, with sub-micromolar affinities. Additionally, we determined the binding mode of six of the best compounds using protein crystallography, which revealed occupation of an underutilised region of the active site.
Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA-binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer cells exploit this intrinsic DNA repair network to counteract many types of chemotherapies. Now, advances in the molecular biology of cancer has paved the way for the combination of DDR inhibitors such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and agents that induce high levels of DNA replication stress or single-strand break damage for synergistic cancer cell killing. In this review, we summarise early-stage, preclinical and clinical findings exploring platinum and emerging ruthenium anti-cancer complexes alongside PARPi in combination therapy for cancer and also describe emerging work on the ability of ruthenium and gold complexes to directly inhibit PARP activity.