Background: Receptor tyrosine kinases (RTKs) are signaling enzymes responsible for the transfer of Adenosine triphosphate (ATP) γ-phosphate to the tyrosine residues substrates. RTKs demonstrate essential roles in cellular growth, metabolism, differentiation, and motility. Anomalous expression of RTK customarily leads to cell growth dysfunction, which is connected to tumor takeover, angiogenesis, and metastasis. Understanding the structure, mechanisms of adaptive and acquired resistance, optimizing inhibition of RTKs, and eradicating cum minimizing the havocs of quiescence cancer cells is paramount. MainText: Tyrosine kinase inhibitors (TKIs) vie with RTKs ATP-binding site for ATP and hitherto reduce tyrosine kinase phosphorylation, thus hampering the growth of cancer cells. TKIs can either be monoclonal antibodies that compete for the receptor's extracellular domain or small molecules that inhibit the tyrosine kinase domain and prevent conformational changes that activate RTKs. Progression of cancer is related to aberrant activation of RTKs due to due to mutation, excessive expression, or autocrine stimulation. Conclusions:Understanding the modes of inhibition and structures of RTKs is germane to the design of novel and potent TKIs. This review shed light on the structures of tyrosine kinases, receptor tyrosine kinases, tyrosine kinase inhibitors, minimizing imatinib associated toxicities, optimization of tyrosine kinase inhibition in curtailing quiescence in cancer cells and the prospects of receptor tyrosine kinase based treatments.

D614G spike glycoprotein (sgp) mutation in rapidly spreading severe acute respiratory syndrome coronavirus‐2 (SARS‐COV‐2) is associated with enhanced fitness and higher transmissibility in new cases of COVID‐19 but the underlying mechanism is unknown. Here, using atomistic simulation, a plausible mechanism has been delineated. In G614 sgp but not wild type, increased D(G)614‐T859 Cα‐distance within 65 ns is interpreted as S1/S2 protomer dissociation. Overall, ACE2‐binding, post‐fusion core, open‐state and sub‐optimal antibody‐binding conformations were preferentially sampled by the G614 mutant, but not wild type. Furthermore, in the wild type, only one of the three sgp chains has optimal communication route between residue 614 and the receptor‐binding domain (RBD); whereas, two of the three chains communicated directly in G614 mutant. These data provide evidence that D614G sgp mutant is more available for receptor binding, cellular invasion and reduced antibody interaction; thus, providing framework for enhanced fitness and higher transmissibility in D614G SARS‐COV‐2 mutant.

COVID‐19 pandemic is currently decimating the world's most advanced technologies and largest economies and making its way to the continent of Africa. Weak medical infrastructure and over‐reliance on medical aids may eventually predict worse outcomes in Africa. To reverse this trend, Africa must re‐evaluate the only area with strategic advantage; phytotherapy. One of the many plants with previous antiviral potency is against RNA viruses is Aframomum melegueta. In this study, one hundred (100) A. melegueta secondary metabolites have been mined and computational evaluated for inhibition of host furin, and SARS‐COV‐2 targets including 3C‐like proteinase (Mpro/3CLpro), 2′‐O‐ribose methyltransferase (nsp16) and surface glycoprotein/ACE2 receptor interface. Silica‐gel column partitioning of A. melegueta fruit/seed resulted in 6 fractions tested against furin activity. Diarylheptanoid (Letestuianin A), phenylpropanoid (4‐Cinnamoyl‐3‐hydroxy‐spiro[furan‐5,2′‐(1′H)‐indene]‐1′,2,3′(2′H,5H)‐trione), flavonoids (Quercetin, Apigenin and Tectochrysin) have been identified as high‐binding compounds to SARS‐COV‐2 targets in a polypharmacology manner. Di‐ethyl‐ether (IC50 = 0.03 mg/L), acetone (IC50 = 1.564 mg/L), ethyl‐acetate (IC50 = 0.382 mg/L) and methanol (IC50 = 0.438 mg/L) fractions demonstrated the best inhibition in kinetic assay while DEF, ASF and MEF completely inhibited furin‐recognition sequence containing Ebola virus‐pre‐glycoprotein. In conclusion, A. melegueta and its secondary metabolites have potential for addressing the therapeutic needs of African population during the COVID‐19 pandemic.

Ebola virus (EboV) is currently ravaging West Africa with estimated case fatality rate of 52%. Currently, no drug treatment is available and immunoglobulin therapy is still at the rudimentary stage. For anti-EboV drug development, druggable viral and host protein targets, including human Furin are under intense investigation. Here, molecular dynamics simulation was performed on Apo-Furin, meta-guanidinomethyl-Phac-RVR-Amba-bound, and two EboV glycoprotein (GP) 494-TGGRRTRREA-503/Furin complexes (Accurate and one amino acid shift alignment). The results of the simulation established ligand-induced desolvation of Furin active site and structural compactness. Accurately aligned EboV-GP peptide exhibited a tighter binding mode with Furin and showed 1.5- and 3.0-fold MMPBSA binding free energy estimate compared with the displaced peptide and inhibitor, respectively. The difference in free energy was traced to the difference in contribution of threonine residues of the peptides. Furthermore, Furin subsites I conferred substrate specificity and ligand binding accuracy. Accurately aligned peptide trapped active site His194 side chain into gauche (-) (+60(o)) χ1-dihedral compared with gauche+ (-60(o)) in other biosystems while Asp153 is trapped in gauche+ (-60(o)) in ligand bound not Apo state. Ramachandran plot showed that the scissile Arg8 of the accurately aligned peptide showed β conformation distribution as apposed to 310R, αL, and 310L. Finally, the active site proximal Na(+) binding is dependent on substrate peptide occupancy of the active site but detaches in the absence of a ligand. In conclusion, Furin might represent candidate drug target for Ebola virus disease treatment via therapeutic target of the active site and Na(+) binding pocket.