Classes of Mormordicoside with potent and selective tumor cell growth inhibitory activity: prediction of Pyruvate kinase muscle isozyme 2 (PKM 2) and Anti-apoptotic Myeloid leukemia 1 (MCL1) inhibitor through machine learning.

Abstract

Background The difficulty in treating cancer resides in the ability to target abnormal proliferation while protecting normal proliferation, a feat that necessitates a thorough comprehension of both the normal and malignant mechanisms that promote cell growth and proliferation. Targeting cell death signaling pathways such as glycolytic and mitochondrial apoptosis is hallmark of many cancers the aim in which this research is ready to evaluate. Methods Atomistic molecular dynamics simulation of top hits after molecular docking and ADMET profiling of the ligands were performed for main protease-hit complexes. Results Docking scores of ligands used against PKM2 ranges from – 9.36 to – 12.1 kcal/mol, wherein, Mormordicoside-F2 had the highest score (-12.1kcal/mol) performing better than the FDA approved drug Benserazide(-7kcal/mol). Likewise, the scores ranged between – 8.51 and – 12.05kcal/mol for Anti-apoptotic Myeloid leukemia 1 (MCL-1), with Mormordicoside-F1 being the highest ranked compound performing better than the FDA approved drug Venetoclax(-8.6 kcal/mol). The RMSD plots obtained depicted stable trajectories with consistent and minor fluctuations implying that the protein (PKM2 and MCL1) backbone underwent minor structural perturbations. In addition, several significant peaks of increased fluctuations (RMSF) were also observed, indicating their increased interaction potential implying that the ligands could adapt effectively in the binding pocket of the protein. SASA analysis results shows that ligands used retained inside their shallow binding pocket. The phylogenetic tree obtained implies likelihood of reoccurring result of the Insilco profiling. Conclusion This research unveils that Mormordicoside F1 shows acceptable stability with Anti-apoptotic Myeloid leukemia 1 (MCL-1), likewise Mormordicoside F2 against PKM2. These hits may offer a more advantageous repurposing alternative.