© 2021 Elsevier B.V.A set of molecular descriptors have been calculated and used in order to identify the most reactive parts of bioactive molecules, brucine (BRU) and colchicine (COL). Comparison of various physico-chemical properties has been performed in order to investigate stability. Besides global and local reactive parameters, attention has been paid to the autoxidation properties and reactivity with water molecules. Molecular Dynamics (MD) simulations and docking results show that BRU and COL bound D-lactate dehydrogenase enzyme are less fluctuating and more stable than the apo protein. To reveal the autoxidation and reactivity with water molecules Density Functional Theory (DFT) simulation has been carried out for the interactions and charge transfer mechanism of water molecules on different sites of bio-molecules, BRU and COL. This may help to further understand and identify the most active parts of the bio-molecules, BRU and COL. We have presented various interaction parameters, e.g., adsorption energy, molecular distance, charge transfer and orbital interactions. The sites with higher adsorption energy and charge transfer signify better reactivity with water.