3.5 In-silico molecular docking of
oligosaccharyltransferase to explore its role as therapeutic target
We performed in silico molecular docking of STT3A and STT3B with
a library of 89 FDA approved drugs (Table S2 ). STT3A and STT3B
are the catalytic subunits of Oligosaccharyltransferase, STT3A-OST
catalyses co-translational N-glycosylation while STT3B-OST catalyses
post-translational glycosylation. NGI-1 is a known inhibitor of both
oligosaccharyltransferase (OST) isoforms; STT3A-OST and STT3B-OST.
Therefore, it was used as a positive control to set the threshold for
binding energy and to identify the active site. NGI-1 interacted with
STT3A and STT3B with binding energy of -8.3 kcal/mol and -7.7 kcal/mol
respectively. In total 44 drugs out of 89 showed lower binding energy
than NGI-1 for STT3A while for STT3B, 52 drugs showed lower BE and 46
drugs were common between STT3A and STT3B. Top 5 drugs which showed
lower binding energy than the control and share same binding pockets
were selected. The list of top 5 drug candidates with their binding
energy is given in (Table S3). Irinotecan and Entrectinib
interacted with both STT3A and STT3B with lowest binding energy(Figure 5) . Irinotecan is a camptothecin derivative that has a
broad-spectrum antitumor activity against a variety of tumors. It was
first approved for the treatment of metastatic colorectal cancer (CRC).
Combining irinotecan with other drugs increases the overall survival in
CRC patients (39). Irinotecan binds to STT3A with a binding energy of
-11 kcal/mol and to STT3B with 10.6 kcal/mol. Entrectinib is another
drug which has shown higher affinity, it binds with STT3A with -10.7
kcal/mol and with STT3B with -10.6 kcal/mol. Entrectinib is a
multi-target small molecule inhibitor that targets TRK, ROS1 and ALK. It
is approved by the FDA for the treatment of locally advanced or
metastatic solid tumors with NTRK, ROS1 and ALK gene mutations (40).