Cardiovascular diseases (CDs) are a major concern in the human race and one of the leading causes of death worldwide. β-Adrenergic receptors (β1-AR and β2-AR) play a crucial role in the overall regulation of cardiac function. In the present study, structure-based virtual screening, machine learning (ML), and a ligand-based similarity search were conducted for the PubChem database against both β1- and β2-AR. Initially, all docked molecules were screened using the threshold binding energy value. Molecules with a better binding affinity were further used for segregation as active and inactive through ML. The pharmacokinetic assessment was carried out on molecules retained in the above step. Further, similarity searching of the ChEMBL and DrugBank databases was performed. From detailed analysis of the above data, four compounds for each of β1- and β2-AR were found to be promising in nature. A number of critical ligand-binding amino acids formed potential hydrogen bonds and hydrophobic interactions. Finally, a molecular dynamics (MD) simulation study of each molecule bound with the respective target was performed. A number of parameters obtained from the MD simulation trajectories were calculated and substantiated the stability between the protein-ligand complex. Hence, it can be postulated that the final molecules might be crucial for CDs subjected to experimental validation.

Biliary tract cancer (BTC) is constituted by a heterogeneous group of malignant tumors that may develop in the biliary tract, and it is the second most common liver cancer. Human ribonucleotide reductase M1 (hRRM1) has already been proven to be a potential BTC target. In the current study, a de novo design approach was used to generate novel and effective chemical therapeutics for BTC. A set of comprehensive pharmacoinformatics approaches was implemented and, finally, seventeen potential molecules were found to be effective for the modulation of hRRM1 activity. Molecular docking, negative image-based ShaEP scoring, absolute binding free energy, in silico pharmacokinetics, and toxicity assessments corroborated the potentiality of the selected molecules. Almost all molecules showed higher affinity in comparison to gemcitabine and naphthyl salicylic acyl hydrazone (NSAH). On binding interaction analysis, a number of critical amino acids was found to hold the molecules at the active site cavity. The molecular dynamics (MD) simulation study also indicated the stability between protein and ligands. High negative MM-GBSA (molecular mechanics generalized Born and surface area) binding free energy indicated the potentiality of the molecules. Therefore, the proposed molecules might have the potential to be effective therapeutics for the management of BTC.