Background:
N-myc downstream regulated gene 3 (NDRG3) is a newly discovered
oxygen-regulated protein which will bind with L-Lactate in hypoxia and further activate Raf (rapidly
accelerated fibrosarcoma)-ERK (extracellular regulated protein kinases) pathway, promoting
cell growth and angiogenesis.
Methods:
Competitive inhibition on the binding of NDRG3 and L-Lactate may be potentially a
useful strategy for the repression of hypoxic response mediated by NDRG3. The threedimensional
(3D) structure of NDRG3 was built by using homology modeling for its crystal structure
was not available. Then, L-Lactate was docked into NDRG3, from which we knew it bound
with amino acid residues Gln69, His183, Asn189, Ala72 and Pro66 of NDRG3 in the most possible
active sites. Approximately 3000 compounds have been virtually screened and the 6 topranked
compounds were selected as reference molecules to analyze their interaction relationships,
which illustrated that some of them might form electrostatic interaction with Glu70 and Asp187,
π-&π stack with Phe75 and Tyr180, hydrogen bonds with Gly71 and Asn189, hydrophobic effect
with Ala72 and Ile184.
Results:
Novel molecules were designed through structural optimization of the 6 top-ranked compounds
and subsequently their ADMET properties were predicted.
Conclusion:
These molecules may be potential drug candidates for the suppression of hypoxic response
mediated by NDRG3 and targeted therapy for hypoxia-induced diseases.
The Role of Electrostatics in Enzymes: Do Biomolecular Force Fields Reflect Protein Electric Fields?