Mechanistic insights into novel cyano-pyrimidine pendant chalcone derivatives as LSD1 inhibitors by docking, ADMET, MM/GBSA, and molecular dynamics simulation

Abstract

Cancer presents a formidable and complex foe, standing as one of the foremost contributors to disease-related fatalities across the globe. According to data from the Global Cancer Observatory (GLOBOCAN), projections indicate a staggering 28.4 million cases of cancer, encompassing both new diagnoses and deaths, by 2040. Therefore, developing effective and comprehensive treatment approaches for cancer patients is essential and the conventional approved treatments for cancers are associated with various harmful side effects. Our study aims to address the critical and widespread need for alternative therapies that can effectively combat cancer with minimal side effects. The present contribution outlines a targeted approach using Lysine Specific Demethylase 1 (LSD1) to evaluate novel cyano-pyrimidine pendant chalcone derivatives as potential antiproliferative agents. Two sets of novel cyano-pyrimidine pendant chalcone derivatives were produced, and molecular docking was performed on the LSD1 protein. The ligands A1 and B1 belonging to series A and B, respectively, were found to have the highest docking scores of -11.095 and -10.773 kcal/mol, in that order. The ADME and toxicity studies of the ligands showed promising responses with respect to various pharmacokinetic and physicochemical parameters. The Molecular dynamics (MD) simulation results indicated effective diffusion of both complexes inside the protein cavity, facilitated by prominent interactions with various amino acids. Additionally, the complexes displayed high relative binding free energy. The computational screening of ligands indicates that ligands A1 and B1 exhibit potential for further exploration using various in vitro and in vivo techniques. These ligands may then serve as promising leads in the discovery of cancer drugs. The in-silico screening of the novel library of cyano-pyrimidine pendant chalcone derivatives was performed with a combination of molecular docking, MM-GBSA, ADME, toxicity and MD simulation. Molecular docking and MM-GBSA were conducted using the Glide and Prime tools, respectively, of the Schrödinger suite 12.8. The ligands were analysed for ADME using the Swiss ADME, while toxicity risks were evaluated using Osiris Property Explorer. Additionally, a 400ns MD simulation of LIGA1 and LIGB1 against the protein LSD1 was performed using the Desmond tool of Schrödinger suite 12.8 to validate the docking results and analyse the behaviour and stability of the complexes.

Keywords: Cancer; Chalcone; Cyano-pyrimidine; LSD1; Molecular docking; Molecular dynamics.

Graphical abstract

Fig. 1

LSD1 inhibitors in clinical trails.

Fig. 2

Marketed drugs containing basic moiety constructs.

Fig. 3

2D and 3D binding interactions of ligand A1 and the 2DW4 complex.

Fig. 4

2D and 3D binding interactions of ligand B1 and the 2DW4 complex.

Fig. 5

A: Fluctuations of Protein RMSD and B: Ligand RMSD of the LIGA1-2DW4 and the LIGB1-2DW4 complex.

Fig. 6

Protein RMSF of A: LIGA1-2DW4 complex and B: LIGB1-2DW4 complex.

Fig. 7

Protein Ligand contacts histogram of A: LIGA1-2DW4 complex and B: LIGB1-2DW4 complex.

Fig. 8

A: rGyr and B: SASA of the LIGA1-2DW4 complex and the LIGB1-2DW4 complex.