Recent Advances in Therapeutic Approaches Against Ebola Virus Infection.

BACKGROUND: Ebola virus (EBOV) is a genus of negative-strand RNA viruses belonging to the family Filoviradae that was first described in 1976 in the present-day Democratic Republic of the Congo. It has intermittently affected substantial human populations in West Africa and presents itself as a global health menace due to the high mortality rate of patients, high transmission rate, difficult patient management, and the emergence of complicated autoimmune disease-like conditions post-infection. OBJECTIVE: EBOV or other EBOV-like species as a biochemical weapon pose a significant risk; hence, the need to develop both prophylactic and therapeutic medications to combat the virus is unquestionable. METHODS: In this review work, we have compiled the literature pertaining to transmission, pathogenesis, immune response, and diagnosis of EBOV infection. We included detailed structural details of EBOV along with all the available therapeutics against EBOV disease. We have also highlighted current developments and recent advances in therapeutic approaches against Ebola virus disease (EVD). DISCUSSION: The development of preventive vaccines against the virus is proving to be a successful effort as of now; however, problems concerning logistics, product stability, multi- dosing, and patient tracking are prominent in West Africa. Monoclonal antibodies that target EBOV proteins have also been developed and approved in the clinic; however, no small drug molecules that target these viral proteins have cleared clinical trials. An understanding of clinically approved vaccines and their shortcomings also serves an important purpose for researchers in vaccine design in choosing the right vector, antigen, and particular physicochemical properties that are critical for the vaccine's success against the virus across the world. CONCLUSION: Our work brings together a comprehensive review of all available prophylactic and therapeutic medications developed and under development against the EBOV, which will serve as a guide for researchers in pursuing the most promising drug discovery strategies against the EBOV and also explore novel mechanisms of fighting against EBOV infection.

Integrated structure-guided computational design of novel substituted quinolizin-4-ones as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors.

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a known drug target for the development of antimalarial agents. Herein, we presented integrated structure-guided computational strategies for the design of novel quinolizin-4-ones as PfDHODH inhibitors. PROCHECK and ERRAT analysis were performed for the validation of co-crystal structures of PfDHODH enzyme bound to the inhibitors available on PDB. Based on the results, PDB ID: 6i55 was selected for further structure-guided in silico studies. Five featured-based pharmacophore model (AADRR) was generated, and validated using GH scoring (0.74) and ROC analysis (0.94). Validated structure-based model was further used as a 3D search query to screen the ZINC database. Retrieved database compounds ZINC00386658, ZINC08439293, and ZINC09089086 were found in agreement with query features based on their highest fitness scores. HTVS, SP and XP docking studies with these retrieved hits demonstrated important interactions (His185. Arg265) with PfDHODH. Mapping of features of the pharmacophore model on these retrieved hits along with the role played by scaffolds and functional groups in docking study helped in the selection of quinolizin-4-one as a main scaffold and different functional groups for the design of novel compounds as PfDHODH inhibitors. In silico ADMET prediction study suggested that designed quinolizin-4-ones are "drug-like" candidates and can be synthesised without too many difficulties. In docking study of newly designed compounds, 8d exhibited the highest docking score of - 12.78 kcal/mol and formed important polar interactions (His185. Arg265) with the PfDHODH. PfDHODH-8d complex showed stable RMSD between 2.5 Å and 3 Å during 100 ns MD simulation study. The RMSD, RMSF and RoG analysis of the PfDHODH-8d complex indicated the absolute stability of the complex. Overall, combined in silico study identified quinolizin-4-ones as selective PfDHODH inhibitors.