Effect of Anti-Retroviral Drug Impurity/Related Substances on the CCR5 and/or CXCR4 Receptors Binding Sites to Revise Resistance Mechanisms in the Clinical Implications Using Molecular Docking Studies.

Background: CCR5 and/or CXCR4 receptors on CD4+ T cell membranes are the active sites for HIV to bind. The different classes of drugs have a unique mechanism of action to cease the virus, but we are concentrating in the first-class i.e. NNRTI that destroys the virus while it binds to the cell surface gp120 protein. The drugs are having several impurities that can be genotoxic and few are reported in the monographs.

Objective: This study proposes the affinity of the impurities to the active site through molecular docking to a receptor (PDB ID 4MBS) from the library of analogs available for antiretroviral drugs. As these drugs are taken for the long term, this study will give a prominent idea for testing the impurities and their genotoxicity.

Methods: We have done molecular docking of 37 impurities and drugs with the GLIDE module of schrodinger software for their binding affinities. In this study, receptor CCR5 and/or CXCR4 is selected containing glycoprotein that mediates virus binding to CD4+ T cell.

Results: Didanosine E and Zidovudine D shows maximum and minimum score respectively. The selected impurities were interfering with the active binding site that may lead to any ADR or reduce the effect of API.

Conclusion: Conclusively, a significant role is played by Protein-Ligand interaction in structuralbased designing. Summarizing that there might be a genotoxicity effect due to competition between API and the impurities. The molecular docking was used to study the binding mechanism and to establish the docking score along with the activity. The outcome of the study can be used to design and development of novel compounds having genotoxicity.