Double Variational Binding--(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands

Abstract

Variational quantitative binding-conformational analysis for a series of anti-HIV pyrimidine-based ligands is advanced at the individual molecular level. This was achieved by employing ligand-receptor docking algorithms for each molecule in the 1,3-disubstituted uracil derivative series that was studied. Such computational algorithms were employed for analyzing both genuine molecular cases and their simplified molecular input line entry system (SMILES) transformations, which were created via the controlled breaking of chemical bonds, so as to generate the longest SMILES molecular chain (LoSMoC) and Branching SMILES (BraS) conformations. The study identified the most active anti-HIV molecules, and analyzed their special and relevant bonding fragments (chemical alerts), and the recorded energetic and geometric docking results (i.e., binding and affinity energies, and the surface area and volume of bonding, respectively). Clear computational evidence was also produced concerning the ligand-receptor pocket binding efficacies of the LoSMoc and BraS conformation types, thus confirming their earlier presence (as suggested by variational quantitative structure-activity relationship, variational-QSAR) as active intermediates for the molecule-to-cell transduction process.

Keywords: 1,3-disubstituted uracil derivative; SMILES; anti-HIV; chemical binding affinity; interacting amino acid; ligand-receptor docking.

Figure 1

Pyrimidine derivatives used in the treatment of HIV/AIDS; the emphasized molecular fragments—also represented in the color red—are studied in this work.

Figure 2

Pyrimidine derivatives which have been tested or have reached in different stages of clinical trials for treatment of HIV/AIDS; the emphasized molecular fragments—also represented in the color red—are studied in this work.

Figure 3

Pyrimidine derivatives already tested as NNRTI; the emphasized molecular fragments—also represented in the color red—are studied in this work. See text for details.

Figure 4

(A) The structure of HIV-1RT with rilpivirine drug bounded in a known place/situs to protein as our molecules; (B) more details on the docking of rilpivirine drug and the molecule no. 25 of Table 1; (C) still a different variant of 1-Click Docking results with molecule 25, yet with dashed surface and without adjacent amino acids; and (D) The PatchDock result of molecule no. 25, with the same color legend: the Genuine, BraS, and LoSMoC as green, red, and blue sticks, respectively.

Figure 5

ContPro [117] results for interacting residues with selected molecules at 3.5 Å by the present Genuine-LoSMoC-BraS double variational procedure, in their relevant configuration(s), see text for details.

Figure 5

ContPro [117] results for interacting residues with selected molecules at 3.5 Å by the present Genuine-LoSMoC-BraS double variational procedure, in their relevant configuration(s), see text for details.

Figure 5

ContPro [117] results for interacting residues with selected molecules at 3.5 Å by the present Genuine-LoSMoC-BraS double variational procedure, in their relevant configuration(s), see text for details.

Figure 6

Flow diagram summary outlining the computational protocol towards double variational procedure in the relevant configuration(s) for the present outlined molecule 29; See text for details.