Rational design of novel pyridine-based drugs candidates for lymphoma therapy

•The combination of structure-based, ligand-based, and pharmacokinetics-based approaches in the rational modeling of novel small pyridine-based compounds as effective allosteric MALT1 protease inhibitors against lymphoma.•Molecular Docking, MM-GBSA free binding energy, and Molecular Dynamics simulation studies are used to explore the stability and compatibility of protein-drug systems.•The rational drug design strategy is used in this study that focuses on MALT1 protease activity, which leads to the discovery of two novel small molecules as promising anti-lymphoma drug candidates. Research efforts to develop an effective drug for lymphoma with minimal side effects are still very slow. To aid the discovery of new lymphoma drug, we led an extensive in silico computational study based on pharmacophore QSAR modeling, DFT, Molecular Docking, ADME-Tox, biophysical simulation approaches such as Molecular Dynamics analysis (MD) and comprehensive MM-GBSA free binding energy computations on a novel series of pyridine derivatives as promising MALT1 allosteric inhibitors (PDB code: 4I1R). The developed QSAR models demonstrated a strong correlation between the 2D/3D structural properties of pyridine derivatives and their biological inhibitory activity against MALT1 protease enzymatic activity. Based on detailed structural characterizations provided by the QSAR modeling, the biological inhibitory activity of four novel small molecules derived from the template molecule S40 (pIC50 = 8.00) was improved. Based on the molecular modeling and computer-aided drug design approaches used in this work, the lead novel compounds C2 (pIC50 > 8, BE = -9.4 kcal/mol, ΔGbind = -58.15 kcal/mol) and C3 (pIC50 > 8, BE = -8.7 kcal/mol, ΔGbind = -51.31 kcal/mol) were identified as optimal candidate allosteric inhibitors for MALT1 compared to the synthesized templates molecules S40 and Thioridazine. Finally, biophysical simulations demonstrated the high stability of the modeled ligands C2 and C3 inside the active pocket of the MALT1 protease in aqueous conditions throughout the 100 ns trajectory of the MD simulations. Thus, small designed hit compounds C2 and C3 can be used as valid references for design new drugs for lymphoma therapy by targeting MALT1 protease enzymatic activity. [Display omitted]