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1.  Synthesis, X-Ray Crystallographic Characterization, and Electronic Structure Studies of a Di-Azide Iron(III) Complex: Implications for the Azide Adducts of Iron(III) Superoxide Dismutase 
Inorganic chemistry  2008;47(13):5762-5774.
We have synthesized and characterized, using X-ray crystallographic, spectroscopic, and computational techniques, a six-coordinate diazide Fe3+ complex, LFe(N3)2 (where L is the tetradentate ligand 7-diisopropyl-1,4,7-triazacyclononane-1-acetic acid), that serves as a model of the azide adducts of Fe3+ superoxide dismutase (Fe3+SOD). While previous spectroscopic studies revealed that two distinct azide-bound Fe3+SOD species can be obtained at cryogenic temperatures depending on protein and azide concentrations, the number of azide ligands coordinated to the Fe3+ ion in each species has been the subject of some controversy. In the case of LFe(N3)2, the electronic absorption and magnetic circular dichroism spectra are dominated by two broad features centered at 21 500 cm−1 (ε ≈ 4000 M−1 cm−1) and ~30 300 cm−1 (ε ≈ 7400 M−1 cm−1) attributed to N3− → Fe3+ charge transfer (CT) transitions. A normal coordinate analysis of resonance Raman (RR) data obtained for LFe(N3)2 indicates that the vibrational features at 363 and 403 cm−1 correspond to the Fe–N3 stretching modes (νFe–N3) associated with the two different azide ligands and yields Fe–N3 force constants of 1.170 and 1.275 mdyne/Å, respectively. RR excitation profile data obtained with laser excitation between 16 000 and 22 000 cm−1 reveal that the νFe–N3 modes at 363 and 403 cm−1 are preferentially enhanced upon excitation in resonance with the N3− → Fe3+ CT transitions at lower and higher energies, respectively. Consistent with this result, density functional theory electronic structure calculations predict a larger stabilization of the molecular orbitals of the more strongly bound azide due to increased σ-symmetry orbital overlap with the Fe 3d orbitals, thus yielding higher N3− → Fe3+ CT transition energies. Comparison of our data obtained for LFe(N3)2 with those reported previously for the two azide adducts of Fe3+SOD provides compelling evidence that a single azide is coordinated to the Fe3+ center in each protein species.
doi:10.1021/ic800073t
PMCID: PMC4316727  PMID: 18533647
2.  CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies 
Journal of clinical pharmacology  2013;53(8):866-877.
Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells. This study evaluated the CYP3A-mediated drug-drug interaction potential of brentuximab vedotin and the excretion of MMAE. Two 21-day cycles of brentuximab vedotin (1.2 or 1.8 mg/kg intravenously) were administered to 56 patients with CD30-positive hematologic malignancies. Each patient also received either a sensitive CYP3A substrate (midazolam), an effective inducer (rifampin), or a strong inhibitor (ketoconazole). Brentuximab vedotin did not affect midazolam exposures. ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, MMAE exposures were lower with rifampin and higher with ketoconazole. The short-term safety profile of brentuximab vedotin in this study was generally consistent with historic clinical observations. The most common adverse events were nausea, fatigue, diarrhea, headache, pyrexia, and neutropenia. Over a 1-week period, ~23.5% of intact MMAE was recovered after administration of brentuximab vedotin; all other species were below the limit of quantitation. The primary excretion route is via feces (median 72% of the recovered MMAE). These results suggest that brentuximab vedotin (1.8 mg/kg) and MMAE are neither inhibitors nor inducers of CYP3A; however, MMAE is a substrate of CYP3A.
doi:10.1002/jcph.116
PMCID: PMC3777854  PMID: 23754575
Clinical Pharmacology; Clinical Trials; Biotechnology; Oncology; Pharmacokinetics and Drug Metabolism
3.  FTFlex: accounting for binding site flexibility to improve fragment-based identification of druggable hot spots 
Bioinformatics  2013;29(9):1218-1219.
Computational solvent mapping finds binding hot spots, determines their druggability and provides information for drug design. While mapping of a ligand-bound structure yields more accurate results, usually the apo structure serves as the starting point in design. The FTFlex algorithm, implemented as a server, can modify an apo structure to yield mapping results that are similar to those of the respective bound structure. Thus, FTFlex is an extension of our FTMap server, which only considers rigid structures. FTFlex identifies flexible residues within the binding site and determines alternative conformations using a rotamer library. In cases where the mapping results of the apo structure were in poor agreement with those of the bound structure, FTFlex was able to yield a modified apo structure, which lead to improved FTMap results. In cases where the mapping results of the apo and bound structures were in good agreement, no new structure was predicted.
Availability: FTFlex is freely available as a web-based server at http://ftflex.bu.edu/.
Contact: vajda@bu.edu or midas@bu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt102
PMCID: PMC3634182  PMID: 23476022
4.  A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma 
Summary
Purpose
Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody–drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Ley) antigen, conjugated to doxorubicin. Ley is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Ley-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients.
Experimental design
Sixty-two patients with recurrent or metastatic NSCLC expressing Ley, one or two prior chemotherapy regimens, and PS ≤ 2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life.
Results
Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A.
Conclusions
SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.
doi:10.1016/j.lungcan.2006.05.020
PMCID: PMC3715069  PMID: 16934909
Immunoconjugate; Targeted therapy; NSCLC; Lewis Y; SGN-15; Monoclonal antibody
5.  FTSite: high accuracy detection of ligand binding sites on unbound protein structures 
Bioinformatics  2011;28(2):286-287.
Motivation: Binding site identification is a classical problem that is important for a range of applications, including the structure-based prediction of function, the elucidation of functional relationships among proteins, protein engineering and drug design. We describe an accurate method of binding site identification, namely FTSite. This method is based on experimental evidence that ligand binding sites also bind small organic molecules of various shapes and polarity. The FTSite algorithm does not rely on any evolutionary or statistical information, but achieves near experimental accuracy: it is capable of identifying the binding sites in over 94% of apo proteins from established test sets that have been used to evaluate many other binding site prediction methods.
Availability: FTSite is freely available as a web-based server at http://ftsite.bu.edu.
Contact: vajda@bu.edu; midas@bu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr651
PMCID: PMC3259439  PMID: 22113084
6.  Robust Identification of Binding Hot Spots Using Continuum Electrostatics: Application to Hen Egg-White Lysozyme 
Journal of the American Chemical Society  2011;133(51):20668-20671.
Binding hot spots, protein regions with high binding affinity, can be identified by using X-ray crystallography or NMR spectroscopy to screen libraries of small organic molecules that tend to cluster at such hot spots. FTMap, a direct computational analogue of the experimental screening approaches, uses 16 different probe molecules for global sampling of the surface of a target protein on a dense grid and evaluates the energy of interaction using an empirical energy function that includes a continuum electrostatic term. Energy evaluation is based on the fast Fourier transform correlation approach, which allows for the sampling of billions of probe positions. The grid sampling is followed by off-grid minimization that uses a more detailed energy expression with a continuum electrostatics term. FTMap identifies the hot spots as consensus clusters formed by overlapping clusters of several probes. The hot spots are ranked on the basis of the number of probe clusters, which predicts their binding propensity. We applied FTMap to nine structures of hen egg-white lysozyme (HEWL), whose hot spots have been extensively studied by both experimental and computational methods. FTMap found the primary hot spot in site C of all nine structures, in spite of conformational differences. In addition, secondary hot spots in sites B and D that are known to be important for the binding of polysaccharide substrates were found. The predicted probe–protein interactions agree well with those seen in the complexes of HEWL with various ligands and also agree with an NMR-based study of HEWL in aqueous solutions of eight organic solvents. We argue that FTMap provides more complete information on the HEWL binding site than previous computational methods and yields fewer false-positive binding locations than the X-ray structures of HEWL from crystals soaked in organic solvents.
doi:10.1021/ja207914y
PMCID: PMC3244821  PMID: 22092261

Results 1-6 (6)