A key feature of many
cancers is the capacity and the propensity to metabolize
glucose to
lactic acid at a very high rate even in the presence of
oxygen. This characteristic was first discovered in 1924 by Otto Heinrich Warburg.
Hexokinase, the first
enzyme in the glycolytic pathway, not only improves the cell's energy supply in malignant cells, but also protects
cancer cells against apoptosis through direct interaction with mitochondria and with the
Voltage Dependent Anion Channel 1 (VDAC1). The
rupture of HK:
VDAC1 protein complex provides a therapeutic opportunity, as this association appears to protect
tumor cells from mitochondrial outer membrane permeabilization, an event that marks the point of no return in multiple pathways leading to cell death. In the absence of a crystallographic structure and in order to perform an in silico screening of possible small molecules able to inhibit the
protein association, we are presenting a computational model of HK-I:VDAC1 complex. It appears as evident how the first 15 N-terminal residues of HK-I interact with the inner part of the barrel of VDAC1 and not with the outside walls, within the mitochondrial membrane as previously believed. This finding is in agreement with the existence of a secondary
ATP binding site in the same N-terminal region of HK-I which seems to have a crucial role in HK-I interaction with VDAC1. This evidence appears to be in accord also with the high levels of
ATP that are found in
cancer cells. Eventually such arrangements may contribute to stabilize the tertiary structure of VDAC1 while shielding from pro-apoptotic factor binding, protecting in a synergic way the tumoral cell from programmed death.