Role of Electrostatic Interactions, Aromaticity, Hydrophobicity In Protein and Protein-Ligand Dynamics

Abstract

The process of drug discovery and development is time and resource consuming. The incorporation of computational facilities to combine chemical and biological aspects helps in drug discovery, design, development and optimization speeds up the process. Advancement in the structural biology and modern bioinformatics helps to design small molecule drug candidates with better biological activity and target specificity. Considering the fact that the protein function depends on its 3D structure, the complexity of a particular disease can be understood by deducing the dysfunctionality at molecular level. This aids the designing of efficient drug molecules. Various non-covalent interactions such as hydrogen bonding, hydrophobic interaction and aromatic interactions plays a key role in stabilizing the energetically-favored ligands at the binding site of the protein. To understand about the various interactions, a number of protein-ligand systems were studied namely, binding affinity of β-alanine derivatives with human G-protein coupled receptors, benzimidazole derivatives with poly ADP-ribose polymerase enzyme and main protease inhibitors for SARS CoV-2 main protease. The results showed that hydrophobicity, aromaticity and electrostatic interactions are crucial for stabilizing ligands at the target site. The nature and strength of non-covalent interactions can alter the binding affinity and efficacy of drug molecules towards the target. Apart from non-covalent interactions, water molecules at the binding site of protein stabilize the binding site as well as the ligand through hydrogen bonding interactions. The molecular level knowledge of protein dynamics and protein-ligand dynamics can have a positive impact on the drug development process and can accelerate the steps of drug designing with reduced cost and time.