CB-0821, a novel CC chemokine receptor 5 (CCR5) inhibitor with improved binding efficacy proposed as anti-HIV candidate: Computational and in vitro approach

The CC Chemokine Receptor 5 (CCR5) serves a pivotal role in human immunodeficiency virus 1 (HIV-1) Infection by acting as a co-receptor and facilitating the binding of the viral envelope glycoprotein (env). Maraviroc (MVC), a Food and Drug Administration-approved monocarboxylic acid amide, is one of the CCR5 inhibitors employed in HIV treatment. Despite the existence of approved drugs, the emergence of drug resistance underscores the necessity for novel compounds to combat resistance and enhance therapeutic efficacy. In this study, CB-0821, identified from the ChemBridge library, emerged as a promising CCR5 Inhibitor. Molecular dynamics simulations indicate comparable dynamic properties for CB-0821 and MVC. In silico comparisons with other CCR5 inhibitors emphasize CB-0821's superior binding affinity, positioning it as a potential lead compound. Evaluations of the dissociation constant (K_i) and absorption, distribution, metabolism, and excretion predictions suggest CB-0821 as a well-tolerated drug. Furthermore, the dose-dependent inhibition of CCR5 by CB-0821 in Peripheral blood mononuclear cells (PBMCs) (ranging from 10 to 200 nM) demonstrates efficacy, coupled with nontoxicity to Vero cells at concentrations up to 500 nM. These results underscore the potential of CB-0821 in HIV Antiviral therapy, calling for additional preclinical validations before advancing to clinical considerations.

CC chemokine receptor 5; bioinformatics; human immunodeficiency virus; molecular dynamic simulation; virtual screening.