Virtual Screening Competitive Inhibitors Against the Binding of NDRG3 and L-Lactate

Competitively inhibiting the binding of NDRG3 (N-myc downstream regulated gene 3) and L-Lactate may be potentially a useful strategy for the repression of hypoxic response mediated by NDRG3. The three-dimensional (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 mainly bound with amino acid residues Asn133, Ala162, His163, His164, Ser235, Pro236 and Ala237 of NDRG3 in the potential active sites. Approximately 3 000 compounds have been virtually screened and the 4 top-ranked compounds were selected as reference molecules to analyze their interaction relationships, which illustrated that some compounds could bind to NDRG3 protein by different forces with different amino acids, occupying the active sites of NDRG3, thereby competitively inhibiting the binding of NDRG3 and L-Lactate. They could form electrostatic force with Lys139, Asp143, His163, Arg203; - stack with His163; hydrophobic effect with Phe165, Ala237; hydrogen bonds with Asn133, Asp135, Gly140, Arg203, Ser235 and Ala237. These compounds may be promising drug candidates for the suppression of hypoxic response mediated by NDRG3 and targeted therapy for hypoxia-induced diseases.