Abstract

Computational molecular design is a useful tool in modern drug discovery. Virtual screening is an approach that docks and then scores individual members of compound libraries. In contrast to this forward approach, inverse approaches construct compounds from fragments, such that the computed affinity, or a combination of relevant properties, is optimized. We have recently developed a new inverse approach to drug design based on the dead-end elimination and A* algorithms employing a physical potential function. This approach has been applied to combinatorially constructed libraries of small-molecule ligands to design high-affinity HIV-1 protease inhibitors [M. D. Altman et al. J. Am. Chem. Soc. 130: 6099–6013, 2008]. Here we have evaluated the new method using the well studied W191G mutant of cytochrome c peroxidase. This mutant possesses a charged binding pocket and has been used to evaluate other design approaches. The results show that overall the new inverse approach does an excellent job of separating binders from non-binders. For a few individual cases, scoring inaccuracies led to false positives. The majority of these involve erroneous solvation energy estimation for charged amines, anilinium ions and phenols, which has been observed previously for a variety of scoring algorithms. Interestingly, although inverse approaches are generally expected to identify some but not all binders in a library, due to limited conformational searching, these results show excellent coverage of the known binders while still showing strong discrimination of the non-binders. Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, such as ipilimumab, have generated measurable immune responses to Melan-A, NY-ESO-1, and gp100 antigens in metastatic melanoma. Vaccination against such targets has potential forimmunogenicity and may produce an effector memory T-cell response. It has been previously determined the effect of CTLA-4 blockador on antigen-specific responses following vaccination. In-depth immune monitoring was performed on three ipilimumab-treated patientsprevaccinated with gp100 DNA (IMF-24), gp100209–217 and tyrosinase peptides plus GM-CSFDNA (IMF-32), or NY-ESO-1 protein plus imiquimod (IMF-11). In previous studies it was shown that peripheral blood mononuclearcells were analyzed by tetramer and/or intracellular cytokine staining following 10-day culturewith HLA-A*0201-restricted gp100209–217 (ITDQVPFSV), tyrosinase369–377 (YMDGTMSQV),or 20-mer NY-ESO-1 overlapping peptides, respectively. It has also been evaluated on the PDBbind v2012 core set where istar platform combining with RF-Score manages to reproduce Pearson’s correlation coefficient and Spearman’s correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. Here, we have discovered for the first time an in silico predicted and computer-aided molecular designed CTLA-4 (YMDGTMSQV) mimic blockador for the increasement of the antigen-specific CD8+ T-cells to the inprevaccinated patients with melanoma.

Keywords

Evaluation, Inverse Molecular Design Algorithm, Model Binding Site, In silico predicted, computer-aided molecular designed CTLA-4 blockador, increasement, antigen-specific CD8+ T-cells, inprevaccinated patients, melanoma, new cluster, algorithms, Large-Scale Protein-Ligand Docking experiment, inverse design, scoring function, protein-ligand interaction, cytochrome c peroxidase, dead-end elimination, drug design.