Will Natural Compounds Fill the Chemotherapeutic Gap in the Mitigation of Chagas Disease? A Mechanistic Perspective at Atomisitc Level

Abstract Background Trypanosoma cruzi, the parasite that causes Chagas disease, spreads to humans and animals through insect vectors that are only found in the Americas, primarily in the impoverished rural areas of Latin America. Up to 8 million individuals in Mexico, Central America, and South America are estimated to be infected with Chagas disease, the majority of whom are unaware of their condition. Infection is a chronic and potentially fatal condition if left untreated. Drugs that are currently on the market were empirically developed more than three decades ago. Purpose As a result, they frequently have severe side effects and low efficacy, especially in the common chronic form of the condition. Hence, this has resulted in searching for alternative therapeutic options to control this disease, and natural products could be explored to this effect. Method We employed molecular dynamics simulation and binding energy analyses to decipher and unravel the mechanistic inhibitory potential of five selected natural compounds as potential inhibitors of T. cruzi glucokinase for treating Chagas disease as an alternative therapy. Results The results revealed that CPD3 (ZINC 000002345225) displayed the highest binding activity, with a total binding energy of -35.16 kcal/mol, compared to other compounds. The PRED approach identified crucial moieties of CPD3 and several molecular interactions prominent in its binding activity, such as Hydrogen Bond, Alkyl, and Pi-Alkyl. ASN 308, GLY 306, LEU 187, THR 185, GLY 184, and ALA 182 played significant roles in the effective binding activity of CPD3, as evidenced in their steady complementary multiple interactions exhibited throughout the simulation period. In this study, we recommend CPD3 as a promising lead compound that can further promote more experimental investigations for the design of drugs for Chagas disease, thereby addressing the limitations of current therapy options. Conclusion These results showed that natural compounds could be potential candidates against the inhibition of T. cruzi glucokinase for treating Chagas disease as an alternative therapy.