Underlying Mechanisms of Allopurinol in Eliminating Renal Toxicity Induced by Melamine-Uric Acid Complex Formation: A Computational Study.

Using molecular dynamics, we address uric acid (UA) replacement by a model small-molecule inhibitor, allopurinol (AP), from its aggregated cluster in a columnar fashion. Experimentally it has been affirmed that AP is efficient in preventing UA-mediated renal stone formation. However, no study has presented the underlying mechanisms yet. Hence, a theoretical approach is presented for mapping the AP, which binds to melamine (MM) and UA clusters. In AP's presence, the higher-order cluster of UA molecules turns into a lower-order cluster, which "drags" fewer MM to them. Consequently, the MM-UA composite structure gets reduced. It is worth noting that UA-AP and AP-MM hydrogen-bonding interactions often play an essential role in reducing the UA-MM cluster size. Interestingly, an AP around UA makes a pillar-like structure, confirmed by defining the point-plane distribution function. The decomposition of the preferential interaction by Kirkwood-Buff integral into different angles like 0°-30°, 30°-60°, and 60°-90° firmly establishes the phenomenon mentioned above. However, the structural order for such π-stacking interactions between AP and UA molecules is not hierarchical but rather more spontaneous. The driving force behind UA-AP-MM composite formation is the favorable complexation energy that can be inferred by computing pairwise binding free energies for all possible combinations. Performing enhanced sampling and quantum calculations further confirms the evidence for UA degradation.