increases the chance of identifying cure for disease within shortened time [59]. One
of the proteins crucial Ras in a center pathway has been discussed as a case study.
RAt Sarcoma (RAS) protein is a crucial member of the protein family known as
G-proteins. The protein Ras is encoded by one of the most common oncogene in
humans. Ras belongs to GTPase class of the proteins, which possess an inherent
property of GTP hydrolysis activity. Depending on its association with GDP/GTP,
the protein is classified in two distinct conformations: GDP-bound inactive state
and GTP-bound active state [60–62]. The malfunctioning of this protein is known
to play a crucial role in human cancers, especially pancreatic cancer and various
developmental disorders like Costello syndrome, Noonan syndrome [63–65]. The
normal functioning of Ras plays pivotal role in the processes of cell proliferation,
development, differentiation, and signal transduction [63]. The most common of the
Ras mutations are found in pancreatic cancers. Most of the cancers causing
mutations are reported to belong to the conserved switch (Sw I and Sw II) and
GEF-binding regions of the protein. As these regions are involved in protein–
protein interactions and other crucial features, and such mutations directly affect the
Ras protein interaction with other proteins [66, 67]. Studies to understand the
activation and deactivation Ras pathways and comparative studies of wild type and
mutant have been carried out by various groups. A significant low-energy barrier in
case of mutant counterparts of Ras is also well established by various experimental
and computational studies. To further explore the crucial mutations and further
comparison with the wild-type counterpart, computational studies are required to
provide more insight about their dynamics and conformational features.
Furthermore, for K-Ras which is inherently a less druggable molecule, the current
trend of the drug discovery efforts is now directed toward the development of
inhibitors of Ras downstream effectors. Related studies suggest that need of dual
site inhibitors to effectively block oncogenic Ras signaling. Also, triple site inhibitors are also gaining more importance for improved cancer therapeutics.
Considering this as a reference, simulations have been performed to explore and
understand the dynamics of activation pathway of the reported hotspot mutants of
Ras [68]. Similarly, the GTP hydrolysis-mediated inactivation pathways of the
mutant Ras complexes have also been explored. This has helped to provide more
information on the energetics of the mutant Ras complexes by calculating the
energy barrier between the end states of the protein [69]. Molecular docking studies
were carried out on Ras using the approach of drug repurposing with FDAapproved drug molecules database. The literature has suggested three active sites
for Ras as shown in Fig. 15 where ligands can be docked [70]. The residues
involved in three sites are (SITE1) residue 29–37, (SITE2) residue 68–74 and 49–
57, (SITE3) residue 58–74 and 87–91. High-throughput docking has been done
using the DOCK6 software employed in embarrassingly parallel molecular docking
pipeline. Docking-based drug repurposing and simulation study is being carried out
on four Ras systems, namely the wild type, Q61L, G12 V, and G12D mutants, each
for 37 ligands. The multiple trajectories for these systems were visualized using
parallel trajectory visualizer tool, DPICT. For understanding the ligand (drug
candidate) properties, multiple conformations (Fig. 16) were generated using
Turbo Analytics: Applications of Big Data and HPC in Drug …
367
of the proteins crucial Ras in a center pathway has been discussed as a case study.
RAt Sarcoma (RAS) protein is a crucial member of the protein family known as
G-proteins. The protein Ras is encoded by one of the most common oncogene in
humans. Ras belongs to GTPase class of the proteins, which possess an inherent
property of GTP hydrolysis activity. Depending on its association with GDP/GTP,
the protein is classified in two distinct conformations: GDP-bound inactive state
and GTP-bound active state [60–62]. The malfunctioning of this protein is known
to play a crucial role in human cancers, especially pancreatic cancer and various
developmental disorders like Costello syndrome, Noonan syndrome [63–65]. The
normal functioning of Ras plays pivotal role in the processes of cell proliferation,
development, differentiation, and signal transduction [63]. The most common of the
Ras mutations are found in pancreatic cancers. Most of the cancers causing
mutations are reported to belong to the conserved switch (Sw I and Sw II) and
GEF-binding regions of the protein. As these regions are involved in protein–
protein interactions and other crucial features, and such mutations directly affect the
Ras protein interaction with other proteins [66, 67]. Studies to understand the
activation and deactivation Ras pathways and comparative studies of wild type and
mutant have been carried out by various groups. A significant low-energy barrier in
case of mutant counterparts of Ras is also well established by various experimental
and computational studies. To further explore the crucial mutations and further
comparison with the wild-type counterpart, computational studies are required to
provide more insight about their dynamics and conformational features.
Furthermore, for K-Ras which is inherently a less druggable molecule, the current
trend of the drug discovery efforts is now directed toward the development of
inhibitors of Ras downstream effectors. Related studies suggest that need of dual
site inhibitors to effectively block oncogenic Ras signaling. Also, triple site inhibitors are also gaining more importance for improved cancer therapeutics.
Considering this as a reference, simulations have been performed to explore and
understand the dynamics of activation pathway of the reported hotspot mutants of
Ras [68]. Similarly, the GTP hydrolysis-mediated inactivation pathways of the
mutant Ras complexes have also been explored. This has helped to provide more
information on the energetics of the mutant Ras complexes by calculating the
energy barrier between the end states of the protein [69]. Molecular docking studies
were carried out on Ras using the approach of drug repurposing with FDAapproved drug molecules database. The literature has suggested three active sites
for Ras as shown in Fig. 15 where ligands can be docked [70]. The residues
involved in three sites are (SITE1) residue 29–37, (SITE2) residue 68–74 and 49–
57, (SITE3) residue 58–74 and 87–91. High-throughput docking has been done
using the DOCK6 software employed in embarrassingly parallel molecular docking
pipeline. Docking-based drug repurposing and simulation study is being carried out
on four Ras systems, namely the wild type, Q61L, G12 V, and G12D mutants, each
for 37 ligands. The multiple trajectories for these systems were visualized using
parallel trajectory visualizer tool, DPICT. For understanding the ligand (drug
candidate) properties, multiple conformations (Fig. 16) were generated using
Turbo Analytics: Applications of Big Data and HPC in Drug …
367