Journal:JBSD:40

Traditional Chinese medicine application in HIV: An in silico study

Hung-Jin Huanga, Yi-Ru Jianb, Calvin Yu-Chian Chen ^[1]

Molecular Tour
Binding of with is required for HIV replication. When such binding is disrupted, proliferation of HIV is inhibited. This concept was adopted in this study, and the IN-LEDGF structure PDB 2b4j was to search for ligands from traditional Chinese medicine (TCM) that may have potential applications against HIV by disrupting IN-LEDGF binding. TCM compounds 9-Hydroxy-(10E)-octadecenoic acid and Beauveriolide I were found to have higher Dock Scores than D77, a drug demonstrated to inhibit IN-LEDGF binding (Figure 1). Molecular dynamic simulation (40 ns) verified the ability of the TCM candidates to form stable protein-ligand complexes. 9-Hydroxy-(10E)-octadecenoic acid formed stable H-bond with residue A:Lys173 in IN (Figure 2A). Alterations at A:Lys173 have been reported to cause a loss in the binding ability of IN to LEDGF. Binding of 9-hydroxy-(10E)-octadecenoic acid at A:Lys173 could corrupt IN-LEDGF recognition and limit binding Beauveriolide I formed stable interactions with the core LEDGF binding site, particularly with residues B:Gln95 and B:Thr125 of IN, and with Asn367 of LEDGF (Figure 2B). Beauveriolide I could disrupt interface interactions of IN A:Glu170/A:His171 with LEDGF Asp 366, and the hydrophobic contact of IN B:Leu102, B:Ala-128, B:Ala129, B:Trp132, A:Thr174, B:Met178 with LEDGF Ile365. On a larger scale, both TCM candidates induced structural changes resulting in the gradual loss of stabilizing α-helices in IN (Figure 3). Relaxation of α-helices by 9-hydroxy-(10E)-octadecenoic acid were observed at A:Lys186-A:Ile208, B:Gly140-Asp167, and B:Gly197-B:Ile208 (top1_cluster.pdb; top1_cluster.png). When Beauveriolide I was docked into IN, α-helices lost over MD were observed at A:Asn184-A:Gly197, B:Thr93-Glu96, and B:Phe:139-B:Gly149 (top2_cluster.pdb; top2_cluster.png). These structural changes were similar to those caused by D77 (D77_cluster.pdb; D77_cluster.pdb). In summary, ability of 9-hydroxy-(10E)-octadecenoic acid and Beauveriolide I to exhibit good affinity (stable receptor binding) and efficacy (predicted bioactivity), in addition to the ability of the TCM candidates to induce structural instability to IN indicate that the TCM candidates might be good drug-like compounds for the development of HIV drugs.