ALK tyrosine kinase ALK TK is an important target in the development of anticancer drugs. In the present work, we have performed a QSAR analysis on a dataset of 224 molecules in order to quickly predict anticancer activity on query compounds. Double cross validation assigns an upward plunge to the genetic algorithm–multi linear regression (GA-MLR) based on robust univariate and multivariate QSAR models with high statistical performance reflected in various parameters like, fitting parameters; R² = 0.69–0.87, F = 403.46–292.11, etc., internal validation parameters; Q²_LOO = 0.69–0.86, Q²_LMO = 0.69–0.86, CCC_cv = 0.82–0.93, etc., or external validation parameters Q²_F1 = 0.64–0.82, Q²_F2 = 0.63–0.82, Q²_F3 = 0.65–0.81, R²_ext = 0.65–0.83 including RMSE_tr < RMSE_cv. The present QSAR evaluation successfully identified certain distinct structural features responsible for ALK TK inhibitory potency, such as planar Nitrogen within four bonds from the Nitrogen atom, Fluorine atom within five bonds beside the non-ring Oxygen atom, lipophilic atoms within two bonds from the ring Carbon atoms. Molecular docking, MD simulation, and MMGBSA computation results are in consensus with and complementary to the QSAR evaluations. As a result, the current study assists medicinal chemists in prioritizing compounds for experimental detection of anticancer activity, as well as their optimization towards more potent ALK tyrosine kinase inhibitor.

The aldose reductase (AR) enzyme is an important target enzyme in the development of therapeutics against hyperglycaemia induced health complications such as retinopathy, etc. In the present study, a quantitative structure activity relationship (QSAR) evaluation of a dataset of 226 reported AR inhibitor (ARi) molecules is performed using a genetic algorithm – multi linear regression (GA-MLR) technique. Multi-criteria decision making (MCDM) analysis furnished two five variables based QSAR models with acceptably high performance reflected in various statistical parameters such as, R² = 0.79–0.80, Q²_LOO = 0.78–0.79, Q²_LMO = 0.78–0.79. The QSAR model analysis revealed some of the molecular features that play crucial role in deciding inhibitory potency of the molecule against AR such as; hydrophobic Nitrogen within 2 Å of the center of mass of the molecule, non-ring Carbon separated by three and four bonds from hydrogen bond donor atoms, number of sp2 hybridized Oxygen separated by four bonds from sp2 hybridized Carbon atoms, etc. 14 in silico generated hits, using a compound 18 (a most potent ARi from present dataset with pIC₅₀ = 8.04 M) as a template, on QSAR based virtual screening (QSAR-VS) furnished a scaffold 5 with better ARi activity (pIC₅₀ = 8.05 M) than template compound 18. Furthermore, molecular docking of compound 18 (Docking Score = –7.91 kcal/mol) and scaffold 5 (Docking Score = –8.08 kcal/mol) against AR, divulged that they both occupy the specific pocket(s) in AR receptor binding sites through hydrogen bonding and hydrophobic interactions. Molecular dynamic simulation (MDS) and MMGBSA studies right back the docking results by revealing the fact that binding site residues interact with scaffold 5 and compound 18 to produce a stable complex similar to co-crystallized ligand's conformation. The QSAR analysis, molecular docking, and MDS results are all in agreement and complementary. QSAR-VS successfully identified a more potent novel ARi and can be used in the development of therapeutic agents to treat diabetes.

Using 84 structurally diverse and experimentally validated LSD1/KDM1A inhibitors, quantitative structure–activity relationship (QSAR) models were built by OECD requirements. In the QSAR analysis, certainly significant and understated pharmacophoric features were identified as critical for LSD1 inhibition, such as a ring Carbon atom with exactly six bonds from a Nitrogen atom, partial charges of lipophilic atoms within eight bonds from a ring Sulphur atom, a non-ring Oxygen atom exactly nine bonds from the amide Nitrogen, etc. The genetic algorithm–multi-linear regression (GA-MLR) and double cross-validation criteria were used to create robust QSAR models with high predictability. In this study, two QSAR models were developed, with fitting parameters like R² = 0.83–0.81, F = 61.22–67.96, internal validation parameters such as Q²_LOO = 0.79–0.77, Q²_LMO = 0.78–0.76, CCC_cv = 0.89–0.88, and external validation parameters such as, R2ext = 0.82 and CCCex = 0.90. In terms of mechanistic interpretation and statistical analysis, both QSAR models are well-balanced. Furthermore, utilizing the pharmacophoric features revealed by QSAR modelling, molecular docking experiments corroborated with the most active compound’s binding to the LSD1 receptor. The docking results are then refined using Molecular dynamic simulation and MMGBSA analysis. As a consequence, the findings of the study can be used to produce LSD1/KDM1A inhibitors as anticancer leads.