Molecular docking and dynamics simulation analysis of the human FXIIa with compounds from the Mcule database.

The human factor XIIa is a serine protease enzyme that is implicated in the pathological thrombosis. This coagulation factor represents an interesting molecular target to design safer antithrombotic agents without adversely influencing physiological hemostasis. Therefore, it is of interest to virtually screen the human factor XIIa crystal with millions of compounds in Mcule database in order to identify potential inhibitors. For this purpose, both molecular docking and dynamics simulation were employed to identify potential hits. Also, various predictive approaches were utilized to estimate chemical, pharmacokinetics and toxicological features for the top hits. As such, we report here that compound 4 (1-(4-benzylpiperazin-1-yl)-2-[5-(3,5-dimethylpyrazol-1-yl)-1,2,3, 4-tetrazol-2-yl]ethanone) may be a potential ligand against the human factor XIIa for further consideration in the design and development of novel antithrombotic agents.

Molecular docking and dynamics simulation analysis of nucleoprotein from the Crimea-Congo hemorrhagic fever virus strain Baghdad-12 with FDA approved drugs.

Crimea-Congo hemorrhagic fever virus is considered a potential public health threat due to the high case fatality ratio of the disease hemorrhagic phase and absence of approved vaccines or antiviral agents. Therefore, it is of interest to screen FDA approved drugs against the nucleoprotein crystal of Crimea-Congo hemorrhagic fever virus strain Baghdad-12 by using molecular docking and dynamics simulation. Hence, we report that the beta receptor blocker Nebivolol and the antihistamine Loratadine may bind to RNA binding region on nucleoprotein for further consideration in drug design and development.

Towards the design of epitope candidates for Coronavirus 2.

The severe acute respiratory syndrome coronavirus-2, formerly known as 2019 novel coronavirus, is a pandemic public health threat. This beta coronavirus potentially infects the alveolar cells of the lung leading to pneumonia. The disease may progress into acute respiratory distress syndrome especially in elderly patients with comorbidities. Therefore, it is of interest to design and develop candidates for treatment, therapy and prevention. The spike glycoprotein of the virus known to potentially interact with angiotensin converting enzyme 2 as a cell entry receptor is a suitable candidate for further consideration as vaccine and treatment candidate. Hence, we screened the spike protein of coronavirus-2 for potential B-cell and T-cell epitopes for further deliberation. Thus, we document several peptides on the spike protein with predicted high antigenicity, low allergenicity and good stability against selected proteases. The linear B-cell epitope with sequence 'GFNCYFPLQSYGF' is of particular interest in this context towards the design and development of short peptide vaccine candidates for combat and care against the virus.

Molecular docking and dynamics simulation of FDA approved drugs with the main protease from 2019 novel coronavirus.

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.

Molecular docking enabled updated screening of the matrix protein VP40 from Ebola virus with millions of compounds in the MCULE database for potential inhibitors.

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-tetraazatetracyclo[7.7.0.02,7.011,15] hexadeca-1(16), 2(7),3,5,8,12,14-heptaen-8-ol)) 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.