Multi-target Polypharmacology of 4-aminoquinoline Compounds against Malaria, Tuberculosis and Cancer.

BACKGROUND: Polypharmacology means drugs having interactions with multiple targets of a unique disease or many disease pathways. This concept has been greatly appreciated against complex diseases, such as oncology, CNS disorders, and anti-infectives. METHODS: The integration of diverse compounds available on public databases initiates polypharmacological drug discovery research. Immunocompromised patients may suffer from complex diseases. Multiple-component drug formulations may produce side effects and resistance issues due to unintended drug-target interactions. RESULTS: Polypharmacology remains a novel avenue to propose a more effective and less toxic treatment. The 4-amino quinoline scaffold has become an important construction motif for the development of new drugs against lifestyle diseases like cancer and infectious diseases like tuberculosis and malaria. CONCLUSION: The present study is an attempt to explore the polypharmacological effects of 4- aminoquinoline drugs to combat malaria, cancer, and tuberculosis.

Repositioning of RdRp Inhibitors Against HCV NS5B Polymerase Utilizing Structure-Based Molecular Docking.

OBJECTIVE: Hepatitis C Virus (HCV) is very dreadful as it can attack an estimated 71 million people around the world. The World Health Organization (WHO) reported that every year about 399000 people die due to HCV caused by chronic cirrhosis and liver cancer globally. There are many drugs available for the treatment of HCV. But drug resistance and toxicity are major issues. The quest for potential drugs utilizing repositioning would be a very useful and economical method to combat HCV. METHODS: One of the most common HCV targets is RNA-dependent RNA polymerase (RdRp). The RdRp is common in HCV, Dengue virus (DENV), Zika virus (ZIKV), and Yellow fever virus (YFV) belonging to the same family of Flaviviridae. An attempt has been made in the present study to reposition different DENV, ZIKV, and YFV RdRp inhibitors against HCV NS5B polymerase utilizing structure-based molecular docking which explores the affinity and mode of binding of these RdRp inhibitors. RESULTS: Several 87 compounds having dengue, yellow fever and zika RdRp inhibitory activities have been taken into consideration for the screening of potential RdRp leads utilizing docking simulation, which focuses on the affinity and mode of binding of sofosbuvir diphosphate, a standard HCV, RdRp inhibitor. CONCLUSION: The compounds 6 (N-sulfonylanthranilic acid derivative), 17 (R1479), 20 (DMB220), 23 (FD-83-KI26), 40 (CCG-7648), 50 (T-1106), 65 (mycophenolic acid), and 69 (DMB213) exhibited docking score within the range of -7.602 to -8.971 Kcal/Mol having almost same mode of interaction as compared to the reference drug molecule. The drugs mentioned above possess satisfactory affinity to bind the hepatitis C viral RdRp and thus may be used to treat the disease. Therefore, these predicted compounds may be potential leads for further testing of anti HCV activity and can be repurposed to combat HCV. The high throughput shotgun of drug repurposing utilizing structure-based docking simulation freeware would be a cost-effective way to screen the potential anti-HCV leads.

To Explore the Potential Targets and Current Structure-based Design Strategies Utilizing Co-crystallized Ligand to Combat HCV.

BACKGROUND: Hepatitis C Virus (HCV) belongs to the Hepacivirus family. HCV has been designated as a very dreadful virus as it can attack the liver, causing inflammation and even may lead to cancer in chronic conditions. It was estimated that 71 million people around the world have chronic HCV infection. World Health Organization (WHO) reported that about 399000 people died because of chronic cirrhosis and liver cancer globally. In spite of the abundance of availability of drugs for the treatment of HCV, however, the issue of drug resistance surpasses all the possibilities of therapeutic management of HCV. Therefore, to address this issue of 'drug-resistance', various HCV targets were explored to quest the evaluation of the mechanism of the disease progression. METHODS: An attempt has been made in the present study to explore the various targets of HCV involved in the mechanism(s) of the disease initiation and progression and to focus on the mode of binding of ligands, which are co-crystallized at the active cavity of different HCV targets. CONCLUSION: The present study could predict some crucial features of these ligands, which possibly interacted with various amino acid residues responsible for their biological activity and molecular signaling pathway(s). Such binding mode may be considered as a template for the high throughput screening and designing of active congeneric ligands to combat HCV.