Designing Ten New Drug Candidates to Block HIV-1 Integrase: A Computational Study Targeting the Enzyme's Magnesium-Dependent Active Site

Abstract

Human Immunodeficiency Virus type 1 (HIV-1) integrase is an essential enzyme that inserts viral DNA into human host cell genomes. Rising clinical resistance to established integrase strand transfer inhibitors (INSTIs) necessitates novel therapeutic strategies. Here, we designed ten de novo small-molecule inhibitors (NIC-01 through NIC-10) using structure-guided drug design targeting high-resolution HIV-1 intasome structures (PDB 6PUT and 5U1C). Built with metal-chelating polycyclic cores and halogenated aromatic tails, these candidates grip catalytic twin magnesium cofactors while engaging active-site residues Pro145, Gln146, and Ser153 alongside terminal viral DNA base dA17. In molecular docking simulations, candidate molecules demonstrated predicted binding free energies between -12.4 and -9.9 kcal/mol, surpassing clinical benchmarks dolutegravir ( 10.1 kcal/mol) and bictegravir (-10.4 kcal/mol). Lead candidate NIC-01 exhibited sub-nanomolar potency (binding free energy -12.4 kcal/mol, $K_i = \mathbf{0.81\text{ nM}}$) with precise metal-coordination geometry. In silico ADMET and drug-likeness profiling confirmed Lipinski compliance, high oral bioavailability, non-mutagenicity, and clear synthetic feasibility.