Pharmacophore-Oriented Identification of Potential Leads as CCR5 Inhibitors to Block HIV Cellular Entry

Abstract

Cysteine-cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists have been investigated in clinical trials, only Maraviroc has been licensed for use in the treatment of HIV patients. This indicates that there is a need for novel CCR5 antagonists. Keeping this in mind, the present study was designed. The active CCR5 inhibitors with known IC₅₀ value were selected from the literature and utilized to develop a ligand-based common feature pharmacophore model. The validated pharmacophore model was further used for virtual screening of drug-like databases obtained from the Asinex, Specs, InterBioScreen, and Eximed chemical libraries. Utilizing computational methods such as molecular docking studies, molecular dynamics simulations, and binding free energy calculation, the binding mechanism of selected inhibitors was established. The identified Hits not only showed better binding energy when compared to Maraviroc, but also formed stable interactions with the key residues and showed stable behavior throughout the 100 ns MD simulation. Our findings suggest that Hit1 and Hit2 may be potential candidates for CCR5 inhibition, and, therefore, can be considered for further CCR5 inhibition programs.

Keywords: CCR5; HIV; inhibitors; molecular docking studies; molecular dynamics simulations analysis; pharmacokinetic properties; pharmacophore modeling.

Figure 1

Illustrative workflow used for the identification of potential CCR5 inhibitors.

Figure 2

The 2D chemical structures of compounds used for the generation of the common feature pharmacophore model.

Figure 3

Chemical characterization of the selected Hypo 1. (A) Green, magenta, and cyan colors represent hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), and hydrophobic (HYP) features, respectively. (B) The inter-feature distance of Hypo 1 displayed in Å.

Figure 4

Pharmacophore-based virtual screening: four databases, namely Asinex, Eximed, Specs, and InterBioScreen, were sorted out using the ROF and ADMET descriptors tool, available in DS.

Figure 5

The 2D chemical structure of identified potential hits.

Figure 6

MD simulation analyses. (A) RMSD plot. (B) Potential energy graph. (C) Analysis of hydrogen bonds. (D) Calculation of binding free energy for MVC, Hit1, and Hit2, calculated using the MM-PBSA method.

Figure 7

Per residue energy contribution of each simulated system of Hit1, Hit2, and reference to binding free energy. (A) Hit1 is represented in green color; (B) Hit2 in violet color; and (C) MVC (reference) is shown in blue color.

Figure 8

The binding mode of (A) MVC, (B) Hit1, and (C) Hit2. MVC, Hit1, and Hit2 are shown in cyan, brown, and green, respectively. The lower panel of the image represents the 2D molecular interactions of (D) MVC, (E) Hit1, and (F) Hit2, with active site residues. The hydrogen bonds are shown with a green dashed line while π-π, π-alkyl, π-cation, π-sulfur, and π-σ interactions are shown as pink, orange, yellow, and purple dashed lines, respectively.