Interactions between proteins and small molecules play important roles in the inhibition of protein function . However, a lack of proper knowledge about non-covalent interactions can act as a barrier towards gaining a complete understanding of the factors that control these associations . To find effective molecules for COVID-19 inhibition, we have quantitatively investigated 143 X-ray crystal structures of the SARS-CoV-2 Mpro protein of coronavirus with covalently or non-covalently bound small molecules (SMs). Our present study is able to explain ordinary and perceptive aspects relating to protein inhibition . The active site of the protein consists of 21 amino acid residues, but only nine are actively involved in the ligand binding process . The H41, M49, and C145 residues have highest priority with respect to interactions with small molecules through hydrogen bond, CH- & #960;, and van der Waals interactions . At the active site, this ranking of amino acids is clear, based on different spatial orientations of ligands, and consistent with the electronic properties . SMs with aromatic moieties that bind to the active site of the protein play a distinct role in the determination of the following order of interaction frequency with the amino acids: CH- & #960 ;> H-bonding> polar interactions . This present study revealed that the G143 and C145 residues play crucial roles in the recognition of the carbonyl functionality of SMs through hydrogen bonding . With this knowledge in mind, an effective inhibitor small-molecule for SARS-CoV-2 Mpro was designed: docking studies showed that the designed molecule has strong binding affinity towards the protein . The non-covalent interactions in the protein-ligand complex are in good agreement with the results obtained from X-ray crystallography . Moreover, the present study focused on weak forces and their influence on protein inhibition, henceforth shedding much light on the essential requirements for moieties that should be present in a good inhibitor and their orientations at the ligand binding site.