Human immunodeficiency virus type 1 (HIV-1) is responsible for the majority of HIV infections worldwide, and we still lack a cure for this infection. Blocking the interaction of HIV-1 and its primary receptor CD4 is one strategy for identifying new anti-HIV-1 entry inhibitors. Here we report the discovery of a novel ligand that can inhibit HIV-1 entry and infection via CD4. Biological and computational analyses of this inhibitor and its analogs, using bioactivity evaluation, Rule of Five (RO5), comparative molecular field analysis (CoMFA)/comparative molecular similarity index analysis (CoMSIA) models, and three-dimensional quantitative structure-activity relationship (3D-QSAR), singled out compound 3 as a promising lead molecule for the further development of therapeutics targeting HIV-1 entry. Our study demonstrates an effective approach for employing structure-based, rational drug design techniques to identify novel antiviral compounds with interesting biological activities.

Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain–Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC₅₀ values at the micro-molar level (8.5 μM and 15.2 μM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure–activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV.

Human immunodeficiency virus-1 (HIV-1) recognizes one of its principal coreceptors, CXC chemokine receptor 4 (CXCR4), on the host cell via the third variable loop (V3 loop) of HIV-1 envelope glycoprotein gp120 during the viral entry process. Here, the mechanism of the molecular recognition of HIV-1 gp120 V3 loop by coreceptor CXCR4 was probed by synthetic peptides containing the full-length V3 loop. The two ends of the V3 loop were covalently linked by a disulfide bond to form a cyclic peptide with better conformational integrity. In addition, to probe the effect of the changed side-chain conformations of the peptide on CXCR4 recognition, an all-D-amino acid analog of the L-V3 loop peptide was generated. Both of these cyclic L- and D-V3 loop peptides displayed comparable binding recognition to the CXCR4 receptor, but not to another chemokine receptor, CCR5, suggesting their selective interactions with CXCR4. Molecular modeling studies revealed the important roles played by many negative-charged Asp and Glu residues on CXCR4 that probably engaged in favorable electrostatic interactions with the positive-charged Arg residues present in these peptides. These results support the notion that the HIV-1 gp120 V3 loop-CXCR4 interface is flexible for ligands of different chiralities, which might be relevant in terms of the ability of the virus to retain coreceptor recognition despite the mutations at the V3 loop.