Molecular docking simulation is the Rational Drug Design (RDD) step that investigates the affinity between protein receptors and ligands. Typically, molecular docking algorithms consider receptors as rigid bodies. Receptors are, however, intrinsically flexible in the cellular environment. The use of a time series of receptor conformations is an approach to explore its flexibility in molecular docking computer simulations, but it is extensively time-consuming. Hence, selection of the most promising conformations can accelerate docking experiments and, consequently, the RDD efforts. It has been previosuly reported that lipopeptides can be used to elicit cytotoxic T lymphocyte (CTL) responses against viral diseases and cancer. In previous scientific projects, it has also been determined that mono-palmitoylated peptides can enhance anti-tumor responses in the absence of adjuvant activity. To investigate whether di-palmitoylated peptides with TLR2 agonist activity are able to induce anti-tumor immunity, it was previously synthesized a di-palmitic acid-conjugated long peptide that contains a murine CTL epitope of HPV E749-57 (Pam2IDG). Pam2IDG stimulated the maturation of bone marrow-derived dendritic cells (BMDCs) through TLR2/6. After immunization, Pam2IDG induced higher levels of T cell responses than those obtained with its non-lipidated counterpart (IDG). Here, we present a novel approach based on GRID molecular interaction fields and the derivative peptide mimicking rationally drug discovery method that has been previously utilized, which may provides a common reference to compare both small molecule ligands and conserved fragment-peptide targeting. Unlike classical pharmacophore elucidation approaches that extract simplistic molecular features, determine those which are common across the data set, and use these features to align the structures and subsequently extracts the common interacting features in terms of their molecular interaction fields, pseudofields, and atomic points, representing the common pharmacophore as a more comprehensive pharmacophoric pseudomolecule. Our fragment-ligand based drug discovery approach is applied to a number of data sets to investigate performance in terms of reproducing the X-ray crystallography-based alignment, in terms of its discriminatory ability when applied to virtual screening and also to illustrate its ability to explain alternative binding modes. As a result we discovered for the first time the GENEA-Tollarepomir-5579, a Toll-like receptor agonist-conjugated peptide-mimetic pharmacophoric multi-targeted agent utilizing a comprehensive source and free tool for assessment of an in silico annotated drug discovery interactive approach for Mining flexible-receptor docking experiments to select promising protein receptor snapshots on the depletion of tumor-associated macrophages by a computer-aided designed canditate druggable Toll-like receptor (Pam2IDG) peptide-domain targeted by a pharmacophoric mimetic agonistic agent.
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