SMALL MOLECULES WHICH CAN KEEP THE ECTODOMAINS OF HUMAN FcγRIIIa CLOSED: THERAPY FOR AUTOIMMUNE THROMBOCYTOPENIA PURPURA?

Comparative analysis of crystal structures of the ectodomains of the unliganded Fc{gamma} receptor A (Fc{gamma}RIIIa), its complex to IgG Fc and two designer proteins named "affimers" revealed that if the two ectodomains of Fc{gamma}RIIIa remain "closed", then they are conformationally incompetent to bind Fc region of antigen or infected cell bound IgG and protect them from degradation in the endosomes. By tightly binding to its ectodomains, these affimers derailed binding of Fc{gamma}RIIIa to Fc portion of IgG leading to latters degradation. This ability to decrease antibody titer suggests use of these affimers as therapeutic interventions in autoimmune conditions like immune thrombocytopenia purpura (ITP) which is caused by autoantibodies against platelets. I queried: are there any small molecules which can dock and lock the ectodomains of Fc{gamma}RIIIa analogous to affimers? Applying MTiOpenScreen on few libraries, I shortlisted 30 drug-like molecules which preferentially docked in the cleft between ectodomains of human Fc{gamma}RIIIa. Their complexes were subsequently analyzed by MD simulations at theoretical pH 7.4 (and 5.7) at 310 K. For all trajectories, we tracked two characteristic molecular descriptors of Fc{gamma}RIIIa: {theta} and {delta}, the angle and distance between the center masses of the two ectodomains, respectively. The values of these descriptors, in conjunction with estimated binding energies from MD simulations allow me to report three new compounds which may act as and/or lead to small molecule interventions in autoimmune conditions like ITP. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/652134v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1ca47d3org.highwire.dtl.DTLVardef@131a4eeorg.highwire.dtl.DTLVardef@431c70org.highwire.dtl.DTLVardef@87b_HPS_FORMAT_FIGEXP M_FIG C_FIG