Design and development of an effective drug to combat the 2019 novel coronavirus remains a challenge. Therefore, it is of interest to study the binding features of 1615 FDA approved drugs with the recently known 2019-nCoV main protease structure having high sequence homology with that from SARS-CoV. We document the binding features of top 10 drugs with the target protein. We further report that Conivaptan and Azelastine are mainly involved in hydrophobic interactions with active site residues. Both drugs can maintain close proximity to the binding pocket of main protease during simulation. However, these data need further in vitro and in vivo evaluation to repurpose these two drugs against 2019-nCoV.

Ebola virus is known for several outbreaks of hemorrhagic fever in West Africa. This RNA virus is linked to high fatality and easy transmission. Recently, an effective vaccine and a monoclonal antibody cocktail have been introduced to combat Ebola virus infection. The matrix protein VP40 of Ebola virus is a known drug target and it is essential for viral life cycle through participation in RNA transcription as well as for the budding of the mature virus. It is known that residues phenylalanine 125 and arginine 134 of VP40 are involved in the interaction with RNA. Therefore, it is of interest to screen VP40 with millions of compounds at the mcule.com database for potential inhibitors. The output hits were ranked according to their minimum binding energy to matrix protein VP40. We further calculated the pharmacokinetics and toxicology properties for the best five hits using several predictive ADME analysis web tools. We report a candidate lead (compound #5: ((10R)-10-(4-hydroxyphenyl)-11,12,14,16-tetra azatetracyclo[7.7.0.0 2,7 .0 11,15 ] hexadeca-1(16), 2(7),3,5,8,12,14-heptaen-8ol)) with high drug-likeness score, promising lead-likeness behaviour and high median lethal dose. The candidate lead compound #5 engages in hydrogen bonding and hydrophobic interactions with VP40 active site residues. Thus, the lead compound #5 is recommended for further in vitro and in vivo validations for further consideration.

Zika virus is a mosquito borne pathogen with a single strand RNA genome. Human infection with this virus is usually asymptomatic, however outbreaks reported in both Pacific region and Latin America have been associated with increase in frequency of microcephaly in newborns and fetuses of infected mothers. Also, the incidence of Guillain-Barré syndrome had also increased among adults with Zika virus infection. Currently, neither vaccine nor antiviral drug has been developed against Zika virus. Structure based virtual screening can be employed, through drug repurposing strategy, to accelerate the identification of potential anti-Zika virus candidates. As such, virtual screening of approved drugs against Zika virus NS2B/NS3 protease can help to recognize new hits capable of hindering viral ability to replicate and evade immune system of the host. In this computational study, we have screened 1615 FDA approved drugs against NS2B/NS3 protease enzyme of Zika virus by using both molecular docking and dynamics simulation. Our virtual screening results indicate that the anti-muscarinic agent Darifenacin and the anti-diarrheal agent Loperamide may have a promising capacity to inhibit Zika virus NS2B/NS3 protease. According to molecular docking and dynamics simulation, these two approved drugs have good binding capacity to NS2B/NS3 as reported by docking energy of binding and MM-PBSA binding energy. In addition, both Darifenacin and Loperamide were able to maintain close proximity to protease crystal throughout simulation period. However, invitro evaluation of these two drugs against Zika virus NS2B/NS3 protease is required to confirm these computational results.

AbstractCoronavirus disease 2019 is a current pandemic health threat especially for elderly patients with comorbidities. This respiratory disease is caused by a beta coronavirus known as severe acute respiratory syndrome coronavirus 2. The disease can progress into acute respiratory distress syndrome that can be fatal. Currently, no specific drug or vaccine are available to combat this pandemic outbreak. Social distancing and lockdown have been enforced in many places worldwide. The spike protein of coronavirus 2 is essential for viral entry into host target cells via interaction with angiotensin converting enzyme 2. This viral protein is considered a potential target for design and development of a drug or vaccine. Previously, we have reported several potential epitopes on coronavirus 2 spike protein with high antigenicity, low allergenicity and good stability against specified proteases. In the current study, we have constructed and evaluated a peptide vaccine from these potential epitopes by using in silico approach. This construct is predicted to have a protective immunogenicity, low allergenicity and good stability with minor structural flaws in model build. The population coverage of the used T-cells epitopes is believed to be high according to the employed restricted alleles. The vaccine construct can elicit efficient and long-lasting immune response as appeared through simulation analysis. This multiepitope-based peptide vaccine may represent a potential candidate against coronavirus 2. However, further in vitro and in vivo verification are required.

Yellow fever is a neglected hemorrhagic disease with a high case fatality rate ranging between 25% and 50% for the hospitalized patients. Yellow fever disease is caused by a zoonotic pathogen known as yellow fever virus. This RNA virus is usually transmitted by mosquitos and it is considered endemic in the tropical regions of South America and Africa. Although an effective vaccine is available for yellow fever virus, no antiviral drug is yet licensed against the disease. Thus, yellow fever virus is still representing a re-emerging threat among unvaccinated individuals in endemic regions. The NS2B-NS3 protease seems to play an important role in yellow fever virus replication cycle. As such, the NS2B-NS3 protease may represent a potential target for structure-based drug design and discovery. In this direction, computational approaches like virtual screening can be utilized to hasten the design of novel antivirals and/ or repurposing an already FDA approved drugs. In this in silico study, an FDA approved drugs library was screened against NS2B-NS3 protease crystal of yellow fever virus. Then the best hits with least energy of binding and ability of hydrogen bonding with key residues of protease active site were then selected and submitted to molecular dynamics simulation. And throughout simulation interval, only Olsalazine was able to stay in close proximity to the active site of protease crystal with least average MM-PBSA binding energy as compared to Dantrolene, Belinostat and Linezolid. This indicates that Olsalazine may have the best capacity to bind to NS2B-NS3 protease and interfere with its activity.