In crystal engineering and medicinal chemistry, cocrystals have enormous applications. Hydrochlorothiazide (HTZ) is found to form cocrystals with picolinic acid (HCP1), pyrazinamide (HPP2) and isonicotinic acid (HIP3). In order to predict energy properties and model potential charge transfer between cocrystal constituents, FMOs energies are used. The frontier molecular orbital analysis reveals the cocrystal’s chemical reactivity and bioactivity. MEP displays the different reactive surfaces in the cocrystals, which is very important when deciding on different biological activities. HCP1, HPP2 and HIP3 have different intermolecular interactions, most of the bonds between atoms are covalent and some of the intramolecular interactions are strong ionic or weak ionic. The non-covalent interactions and identical patterns in the covalent character of weak interactions in title molecules are supported by ELF and LOL. From the MD simulation, the complex structure formed by the HIP3 compound with Mpro was more stable and lower RMSD values than HCP1 and HPP2. The ligands formed strong interactions at SARS-Cov-2 Mpro possible binding sites.