Drug-like screening, molecular docking, molecular dynamics simulations, and binding free energies on the interaction of pyrazole derivatives as inhibitors of lysosomal storage disorders and anticancer activity

Abstract Lysosomal membrane proteins (LAMPs) are a primary target for treating tumors because of their essential role in the cancer life cycle. In this study, some computational approaches, including drug-like screening, molecular docking, and molecular dynamics (MD) simulation studies coupled with the binding free energy, have been conducted to explore the putative binding modes of pyrazole derivatives as inhibitors of lysosomal storage disorders. Certain pyrazole derivatives outperformed typical medications in molecular docking experiments against the LAMPs receptor; among other substances, molecules CID 44555488 and 45,487,645 were deemed ideal. Additionally, these ligands (CID 44555488 and 45,487,645) were projected to be orally accessible in humans after successfully passing five separate drug-likeness criteria. In the end, it was anticipated that these ligands, CID 44555488 and 45,487,645, would have minimal human toxicity and good ADMET properties, particularly in terms of GI absorption and the lack of P-gp interaction. Compounds CID 44555488 and 45,487,645 with high predicted binding affinities were subjected to further molecular dynamics simulations based on the molecular docking data, and their potential binding mechanisms were investigated. The study's description of the structure-based drug design approach will be very helpful in the creation of novel inhibitors with excellent selectivity and potency.