Molecular docking and drug virtual screening of novel small molecule inhibitors of anti-apoptotic proteins for cancer treatment

Bcl-2, an anti-apoptotic protein, is involved in cancer development and progression and has been considered as a promising target in cancer therapy. ABT-199, a Bcl-2 inhibitor, has been approved, as a single agent or in combinations, for the treatment of adult patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or newly diagnosed acute myeloid leukemia (AML) patients with age of 75 years or older. Although most patients can initially benefit from ABT-199 treatment, patients eventually develop resistance majorly due to BCL2 mutations, such as G101V and D103Y, or overexpression of Bcl-xL. Therefore, inhibitors that can target both wild-type and mutant Bcl-2 as well as Bcl-xL have the potential to overcome the resistance mechanisms to ABT-199. LP-118 is a novel inhibitor targeting wild-type Bcl-2, Bcl-2G101V and Bcl-2D103Y mutants, and has moderate activity against Bcl-xL. In preclinical and clinical studies, LP-118 had excellent anticancer activity in animal models and patients with CLL or SLL. However, there is no co-crystal structure information available to show exactly how LP-118 binds to Bcl-2, Bcl-2G101V, Bcl-2D103Y, or Bcl-xL. Molecular docking is one of the most frequently used methods in drug design and discovery, due to its ability to predict the binding-conformation of small molecule ligands to the appropriate target binding site. Using the molecular docking Software ICM-Pro, we are the first to illustrate how LP-118 binds to Bcl-2, Bcl-2G101V, Bcl-2D103Y, and Bcl-xL proteins in 3D. The molecule LP-118 is tightly tugged in the reception pocket of each protein where the interactions, including hydrogen bonding, electrostatic and p-stacking interactions, slightly vary in each case. These knowledge enables a better understanding of the mechanism of actions of LP-118 and provides a foundation for the rational design of future generations of Bcl-2/Bcl-xL inhibitor that will overcome the Bcl-2 mutation resistance. Based on the docking result, we designed over 1,000 analogues of LP-118 by fine-tuning the backbone and substituents on the molecule, used ICM-Pro/VLS software to virtually screen these analogues against Bcl-2, Bcl-2G101V, Bcl-2D103Y, or Bcl-xL, and successfully identified and prioritized 10 top-ranked analogues for chemical synthesis and anticancer activity testing.