Molecular docking as a tool in drug discovery and protein-ligand interaction analysis

Abstract

Molecular docking emerged as an irreplaceable technique of structure-based drug design, revolutionizing the early stages of modern drug discovery since its introduction in the 1980s. Docking is widely used in the rational drug development to estimate binding affinity of newly designed compounds to active sites of selected receptors or enzymes as well as their conformations in the active site. Based on docking studies results, compounds with the lowest binding energy can be selected for synthesis and further experimental evaluation. Crucially, the utility of molecular docking extends far beyond binding affinity for target that will produce pharmacological response. This tool can be used to predict binding to plasma proteins, such as human serum albumin (HSA). providing insight into drug distribution characteristics. Within pharmacokinetic studies, docking is also useful for investigating interactions with drug-metabolizing enzymes, particularly CYP450 complex which catalyzes the metabolism of approximately 70 % to 80 % of clinically relevant drugs. Furthermore, docking can be applied to assess potential interactions with membrane transporters, including P-glycoprotein, which are important determinants of drug absorption and disposition. Ultimately, integrating these in silico calculations allows for the streamlined selection of optimized candidates, bridging the gap between computational prediction and successful experimental evaluation. One example where docking calculations are useful is in the design of selective COX-2 inhibitors with anti-inflammatory effect and reduced gastrointestinal side effects. Conventional NSAIDs are characterized by a high degree of plasma protein binding; therefore, for newly designed compounds it is also highly useful to predict their interaction with HSA.