Identification of novel 2-benzoxazolinone derivatives with specific inhibitory activity against the HIV-1 nucleocapsid protein

Abstract

In this report, we present a new benzoxazole derivative endowed with inhibitory activity against the HIV-1 nucleocapsid protein (NC). NC is a 55-residue basic protein with nucleic acid chaperone properties, which has emerged as a novel and potential pharmacological target against HIV-1. In the pursuit of novel NC-inhibitor chemotypes, we performed virtual screening and in vitro biological evaluation of a large library of chemical entities. We found that compounds sharing a benzoxazolinone moiety displayed putative inhibitory properties, which we further investigated by considering a series of chemical analogues. This approach provided valuable information on the structure-activity relationships of these compounds and, in the process, demonstrated that their anti-NC activity could be finely tuned by the addition of specific substituents to the initial benzoxazolinone scaffold. This study represents the starting point for the possible development of a new class of antiretroviral agents targeting the HIV-1 NC protein.

Inhibitory Effect of Lithospermic Acid on the HIV-1 Nucleocapsid Protein

“…Docking simulations were run according to the protocol described previously [ 15 , 16 , 24 ]. In brief, the ligand was sketched with VIDA (OpenEye Scientific Software) version 4.4.0.4 [ 41 ], while the protonation state was assigned by QUACPAC (OpenEye Scientific Software) version 2.0.0.3 [ 42 ].…”

“…In state-of-the-art progress, three classes of NC inhibitors have been explored: (i) covalent modifiers that bind to NC zinc-coordinating residues or directly to the Zn(II) ions that are crucial for NC activity; (ii) small molecules that bind to nucleic acids targets of the NC; (iii) non-covalent NC binders that compete with nucleic acids for the binding site on the NC surface [ 7 ]. While NC inhibitors of classes (i) and (ii) are most suited as topical microbicides because of their weak selectivity and specificity for the NC that might lead to cytotoxic effects, class (iii) inhibitors have a higher potentiality for being developed as novel anti-HIV-1 systemic drugs [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. It is worth noting that natural products have played an important role in the discovery of NC inhibitors [ 16 , 21 , 23 ].…”

Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

“… 37 To this end, a computational protocol was established and refined in the group of Botta. 14 , 33 , 38 Several NC binding small molecules have already been discovered through this protocol, supporting its validity. 14 , 15 , 33 , 38

Fig.

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“…3 Docking-based predicted binding conformation of 1–4 and guanine within the hydrophobic pocket of the NC. 14 , 33 , 38 A) distal fleximer guanine base ( 1 ), B) proximal fleximer guanine base ( 2 ), C) distal guanine bipyrimidine ( 3 ), D) proximal guanine bipyrimidine ( 4 ) and E) guanine bound to NC. The protein is shown as green cartoon and lines (residues within 4 Å from each ligand are shown and labelled).…”

“…Molecular modeling study was performed as described in previous studies. 14 , 38 Briefly, the NMR structure of the NC in complex with a small molecule inhibitor was used as rigid receptor in molecular docking simulations, 37 which were carried out by the FRED docking program from OpenEye, version 3.0.1. 39 , 40 Ligand conformational analysis was performed with OMEGA from OpenEye.…”