Abstract

Molecular mechanics (MM) methods are computationally affordable tools for screening chemical libraries of novel compounds for sites of P450 metabolism. One challenge for MM methods has been the absence of a consistent and transferable set of parameters for the heme within the P450 active-site. Experimental data indicates that mammalian P450 enzymes vary greatly in the size, architecture, and plasticity of their active sites. Thus, obtaining x-ray based geometries for the development of accurate MM parameters for the major classes of hepatic P450 remains a daunting task. Our previous work with preliminary gas-phase quantum mechanics (QM) derived atomic partial charges, greatly improved the accuracy of docking studies of raloxifene to CYP3A4. Different patterns for substrate docking are also observed depending on the choice of heme model and state. Newly parameterized heme models are tested in implicit and explicitly solvated MD simulations in the absence and presence of enzyme structures, for CYP3A4, and appear to be stable on the nanosecond simulation timescale. The new force field for the various heme states may aid the community for simulations of P450 enzymes and other heme containing enzymes. The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and thereare only a few standard treatments. We conducted a phase I trial to investigate the safety, immune response,and antitumor effect of vaccination with four peptides derived from cancer-testis antigens, with a focus ontheir fluctuations during long-term vaccination until the disease had progressed. A unified statistical model to support local sequence order independent similarity searching for ligand-binding sites and its application to genome-based drug discovery. Bioinformatics, 25, i305–i312.]. These algorithms have been extensively benchmarked and shown to outperform most existing algorithms. Moreover, several predictions resulting from SMAP-WS have been validated experimentally. Thus far SMAP-WS has been applied to predict drug side effects, and to repurpose existing drugs for new indications. SMAP-WS provides both a user-friendly web interface and programming API for scientists to address a wide range of compute intense questions in biology and drug discovery. Here, we have for the first time discovered a multi-epitope mimic poly-pharmacophore to Multiple Peptides Derived from Cancer-Testis Antigens for the maintance of a Specific T-cell Response in Long-term Vaccinated patients with Advanced Biliary Tract Cancer using the BiogenetoligandorolTM based SMAP-WS chemical informatic parallel web service for structural proteome-wide ligand-binding site comparison.

Keywords

Algebraically in silico discovery, multi-epitope, mimic, poly-pharmacophore, Multiple Peptides, Cancer-Testis, Antigens, anti-tumor, pharmaco-agent, Specific T-cell Response, Long-term, Vaccinated patients, Advanced Biliary Tract Cancer, parallel web service, structural proteome-wide, ligand-binding site, comparison, Cytochrome P450 enzymes, heme force field parameters, molecular mechanics, RESP charges, AMBER, drug-metabolism,