Search for Human Lactate Dehydrogenase A Inhibitors Using Structure-Based Modeling

Area of Science:

• Biochemistry and Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Human lactate dehydrogenase A (LDH-A) is crucial for anaerobic metabolism in tumor cells.
• LDH-A is a significant target for developing novel anti-cancer therapies.
• Understanding LDH-A's structure is key for designing effective inhibitors.

Purpose of the Study:

• To generate full-atom models of lactate dehydrogenase A (LDH-A) in complex with NADH and in its apo form.
• To enable structure-based design of novel inhibitors targeting LDH-A.
• To identify potential inhibitors that compete with pyruvate and NADH binding.

Main Methods:

• Generation of full-atom models of human lactate dehydrogenase A.
• Establishment of structural criteria for inhibitor selection.
• Virtual screening of a library of low-molecular-weight compounds.
• Molecular docking simulations to assess binding affinity and pose.

Main Results:

• Full-atom models of LDH-A (apo and NADH-bound) were successfully created.
• Structural criteria for selecting potential inhibitors were defined.
• Virtual screening identified a promising inhibitor candidate, STK381370.
• STK381370's docking pose was stabilized by interactions with loop 96-111, facilitating the open-to-closed conformation transition.

Conclusions:

• The study provides structural insights into LDH-A for rational drug design.
• STK381370 emerged as a potential inhibitor with favorable binding characteristics.
• Targeting LDH-A represents a viable strategy in oncology for developing new cancer treatments.