Current Drug Discovery Technologies - Volume 19, Issue 1, 2022

For a decade, it has been observed that there is a remarkable decrease in the quantum of novel clinically approved drugs, in spite of modernization in the research and development process. We have highlighted repositioning of drugs as a methodology that has found new therapeutic implications for clinically approved drugs but with different indications. This can be considered as an upbringing strategy to deliver timely and cost-effective solutions, which still need exploration for getting over the shortage of novel drugs reaching the market. This review focuses on an activity-based drug repositioning approach, which is used to explore new uses of known drugs that are already approved for specific indications and are now being used for other indications on the basis that a single drug interacts with multiple targets. It also includes current research trends related to drug repositioning, which depends on strong knowledge of medicinal chemistry and involves elucidation of mechanisms of action and validation of novel targets. The review highlights the importance of computational tools and databases of various forms for drug repositioning purposes, which have enhanced the ability to pose reasonable and testable hypotheses. The critical nature of this aspect is obvious in cases where data gathered from in vitro, or animal models do not confirm in subsequent clinical trials. Hence, considering the positive outcomes of drug repositioning, it can be surmised that this approach can serve as a promising one that can develop into a robust drug discovery strategy.

Background: Prunella vulgaris , family Lamiaceae also known as self-heal, has been traditionally used as an expectorant, anti-inflammatory, anti-pyretic, and anti-rheumatic. Due to the widespread distribution of the plant, Vulgaris is also called ‘vulgar’ in Latin adjective meaning common. Objective: The objective of this review was to describe the relevant aspects of phytochemistry and therapeutic uses of different fractions as well as isolated compounds from Prunella vulgaris . An attempt was also made to enumerate the possible leads, e.g . betulinic acid, oleanolic acid, ursolic acid, umbelliferone, scopoletin, esculetin, luteolin, homoorientin, Rosmarinic acid and cinaroside, for further development. Method: For peer-reviewed research literature, we undertook a structured search of bibliographic databases using a focused review question. Scientific databases such as PubMed, Scopus, Science Direct, and Google Scholar were searched. Results: Phytochemistry of Prunella vulgaris (PV) after a thorough literature survey revealed varied and copious metabolites, such as triterpenoids, phenolic acid, sterols, carbohydrates, coumarins, fatty acids, and volatile oils. Many of these compounds have been found to possess a wide range of biological activities per se, including anti-microbial, immunosuppressive, anti-cancer, cardio- protective, anti-allergic and anti-inflammatory activities. Conclusion: Prunella vulgaris is a medicinal plant of immense medicinal importance having a variety of compounds, such as triterpenoids, phenolic acid, sterols, carbohydrates, coumarins, fatty acids, and volatile oils, and diversity in the pharmacological spectrum. The plant could be further exploited to isolate the various biologically active constituents responsible for its activity.

Inebilizumab-cdon (Uplizna™) was currently approved by the United States Food and Drug Administration (USFDA) for the treatment of NMOSD (neuromyelitis optica spectrum disorder). It was developed by Viela Bio (Nasdaq: VIE) USA. Inebilizumab-cdon (formerly MEDI-551) is a humanized antibody, which induces CD19 + B cell depletion by increasing antibody-dependent cell cytotoxicity (ADCC) and cell phagocytosis (ADCP) of effector cells. Various clinical trials exhibit its safe and effective pharmacokinetic and pharmacodynamic profile. In June 2019, Viela Bio submitted Biologics License Application (BLA) to the FDA based on the findings obtained from the N-Momentum trial. This article summarizes the milestones in the development of Inebilizumab-cdon leading to this approval for the treatment of advanced NMOSD.

Background: CCR5 and/or CXCR4 receptors on CD4+ T cell membranes are the active sites for HIV to bind. The different classes of drugs have a unique mechanism of action to cease the virus, but we are concentrating in the first-class i.e. NNRTI that destroys the virus while it binds to the cell surface gp120 protein. The drugs are having several impurities that can be genotoxic and few are reported in the monographs. Objective: This study proposes the affinity of the impurities to the active site through molecular docking to a receptor (PDB ID 4MBS) from the library of analogs available for antiretroviral drugs. As these drugs are taken for the long term, this study will give a prominent idea for testing the impurities and their genotoxicity. Methods: We have done molecular docking of 37 impurities and drugs with the GLIDE module of schrodinger software for their binding affinities. In this study, receptor CCR5 and/or CXCR4 is selected containing glycoprotein that mediates virus binding to CD4+ T cell. Results: Didanosine E and Zidovudine D shows maximum and minimum score respectively. The selected impurities were interfering with the active binding site that may lead to any ADR or reduce the effect of API. Conclusion: Conclusively, a significant role is played by Protein-Ligand interaction in structuralbased designing. Summarizing that there might be a genotoxicity effect due to competition between API and the impurities. The molecular docking was used to study the binding mechanism and to establish the docking score along with the activity. The outcome of the study can be used to design and development of novel compounds having genotoxicity.

Background: The incidence of cognitive decline has been proposed to rise exponentially in the coming years. Therapies targeting molecular pathways involved in the enhancement of memory and energy regulation could be a major breakthrough in the prevention or management of dementia in susceptible populations. Objectives: This study investigated the effects of aqueous extracts of Cola nitida (AECONS) and Garcinia kola (AEGAK) on glutamate level and Na+/K+-ATPase activity in the hippocampus and hypothalamus of male Wistar rats. Methods: Adult male Wistar rats (170-200) were randomly allotted into groups (n=5/group); control (distilled water p.o.), AECONS1 (200 mg/kg), AECONS2 (400 mg/kg), AEGAK1 (200 mg/kg), AEGAK2 (400 mg/kg), AECONS1+AEGAK1 and AECONS2+AEGAK2. The extract was prepared and the administration was done daily for 6 weeks. Results and Discussion: Administration of AECONS or AEGAK increased plasma, hippocampal and hypothalamic glutamate, Na+/K+-ATPase activity, NO, SOD except hippocampal glutamate in AECONS1/AEGAK1, Na+/K+-ATPase activity and SOD in AEGAK1, hypothalamic glutamate and SOD in AECONS1 when compared with control. Besides, MDA level decreased in AEGAK2 and hippocampal but not hypothalamic MDA decreased in AEGAK1 compared with control. However, concomitant administration of AECONS and AEGAK enhanced plasma, hippocampal and hypothalamic biomarkers except hypothalamic MDA level. The present study demonstrates that AECONS and AEGAK synergistically enhance hippocampal and hypothalamic glutamate and Na+/K+- ATPase activity, which are accompanied by NO and SOD-dependent antioxidant enrichment. Conclusion: These findings, therefore, suggest that AECONS+AEGAK could be a better therapeutic candidate in hippocampal-hypothalamic-related neurodegenerative diseases.

Background: Fluorine containing hexahydroquinoline-3-carbonitrile derivatives were found to have potent cytotoxicity. Furthermore, fluorine can modulate pharmacokinetic and pharmacodynamic profile of drugs. Hence, new derivatives containing fluorine were explored as potential cytotoxic agents. Objective: Difluoro substituted compounds containing aromatic/heteroaromatic rings were designed, synthesized and screened for in vitro cytotoxicity on cancer cell lines. The active compounds were subjected to docking on Mcl-1 and ADME/T prediction. Methods: The synthesized compounds were characterized using various spectral techniques like FT-IR, ¹H NMR, ¹³C NMR and Mass spectra. Compounds were screened for cytotoxicity on NCI-60 cell lines at the National Cancer Institute. The active compounds were evaluated additionally by MTT and SRB assay. Results: Compounds (6l and 6o) showed maximum cytotoxicity with (% GI) of 69 and 63.7 at 10 μM drug concentration, respectively. Compound 6i showed potent cytotoxicity with GI50 of 7.2 μM against Ishikawa cell line. Compound 6o was nearly as active as a reference with IC50 of 9.39 μM and 13.54 μM against HT-29 and HCT-116, respectively, and compound 6l also showed equal potency to that of reference with IC50 of 9.66 μM against Caco-2. Compounds 6i, 6o and 6l showed high docking scores, suggesting their cytotoxicity. Furthermore, ADME/T prediction revealed that all the compounds had drug-likeness properties. Conclusion: Enhanced lipophilic interaction of compounds due to the presence of fluorine in compounds 6i and 6l was revealed during the docking study. Compound 6i can be explored as a lead molecule against other endometrial cancer in futuristic drug development.

Background: Despite the introduction of direct oral anticoagulants, the search for new oral anticoagulants remains an urgent task. Objective: By using docking and scoring, based on physical methods, simple chemical rules, methods of synthesis, and activity measurement, develop new low-molecular-weight inhibitors of factor Xa, which are potential anticoagulants. Methods: The development of leads was based on chemical synthesis and structure-based drug design methods. The basic idea was to combine the two approaches: one based on predictive modeling and the other based on the experimental data. Results: In this study, we developed some nanomolar leads. Further chemical modification improved the inhibition constant by more than one order. Discussion: The method proposed in this paper, as well as other methods, includes virtual screening, chemical synthesis, and activity measurement. However, the most time–consuming process in this method (chemical synthesis) was simplified, and the cost was reduced to the extent that was allowed; a very simple chemical reaction was chosen, i.e., the formation of an amide bond. Conclusion: In this work, we demonstrated how using simple chemical rules based on the structurebased drug design, substances with a nanomolar concentration of activity can be developed.

Background: Lung cancer is the leading cause of mortality in India. Adenosine Receptor (AR) has emerged as a novel cancer-specific target. A3AR levels are upregulated in various tumor cells, which may mean that the specific AR may act as a biological marker and target specific ligands leading to cell growth inhibition. Aim: Our aim was to study the efficacy of the adenosine receptor agonist, AB MECA, by in silico (molecular docking) and in vitro (human cancer cells in xenografted mice) studies. Methods: Molecular docking on the AB-meca and TNF-α was performed using AutoDock. A549 Human lung cancer 2 ×10⁶ cells per microliter per mouse injected via intrabronchial route. Rat TNF-α level was assessed by ELISA method. Results: AB Meca's predicted binding energy (beng) with TNF-α was 97.13 kcal/mol, and the compatible docking result of a small molecular inhibitor with TNF-α native ligand beng was 85.76 kcal/mol. In vivo, a single dose of lung cancer cell A549 is being researched to potentiate tumor development. Doxorubicin and A3AR agonist therapies have lowered TNF-alpha levels that were associated with in silico function. The A3AR Agonist showed myeloprotective effects in the groups treated along with doxorubicin. Conclusion: AB MECA’s higher binding energy (beng) with TNF-α mediated reduction of tumor growth in our lung cancer in vivo model suggested that it may be an effective therapy for lung cancer.