Stefania Pfeiffer‐Marek

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Influence of the solvent representation on vibrational entropy calculations: Generalized born versus distance‐dependent dielectric model

Journal of Computational Chemistry (2012)

Hannes Kopitz Daniel A. Cashman Stefania Pfeiffer‐Marek Holger Gohlke

Abstract The harmonic model is the most popular approximation for estimating the “configurational” entropy of a solute in molecular mechanics/Poisson‐Boltzmann solvent accessible surface area (MM/PBSA)‐type binding free energy calculations. Here, we investigate the influence of the solvent representation in the harmonic model by comparing estimates of changes in the vibrational entropies for 30 trypsin/ligand complexes on ligand binding. Second derivatives of Amber generalized Born (GB) solvation models are available in the nucleic acid builder code. They allow one to use these models for the calculation of vibrational entropies instead of using a simpler solvation model based on a distance‐dependent dielectric (DDD) constant. Estimates of changes in the vibrational entropies obtained with a DDD model are systematically and significantly larger, by on average, 6 kcal mol −1 (at T = 300 K), than estimates obtained with a GB model and so are more favorable for complex formation. The difference becomes larger the more the vibrational entropy contribution disfavors complex formation, that is, the larger the ligand is (for the complexes considered here). A structural decomposition of the estimates into per‐residue contributions reveals polar interactions between the ligand and the surrounding protein, in particular involving charged nitrogens, as a main source of the differences. Snapshots minimized with the DDD model showed a structural deviation from snapshots minimized in explicit water that is larger by, on average, 0.5 Å RMSD compared to snapshots that were minimized with GB HCT . As experimental vibrational entropies of biomacromolecules are elusive, there is no direct way to establish a solvent model's superiority. Thus, we can only recommend using the GB harmonic model for vibrational entropy calculations based on the reasoning that smaller structural deviations should point to the implicit solvent model that closer approximates the energy landscape of the solute in explicit solvent. © 2012 Wiley Periodicals, Inc.

Implicit solvation

Conformational entropy

Solvent models

10.1002/jcc.22933

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Citations (19)

Multiparameter Peptide Optimization toward Stable Triple Agonists for the Treatment of Diabetes and Obesity

Advanced Therapeutics (2020)

Andreas Evers Stefania Pfeiffer‐Marek Martin Bossart Ralf Elvert Katrin Lorenz

Abstract Historically, peptide optimization has mainly focused on pharmacological activity. Physicochemical properties have often been evaluated late in discovery, potentially providing molecules with suboptimal stability properties. Often, such issues cannot be overcome by formulation approaches but need additional optimization cycles for a redesign of the peptide. Here, early rational multiparameter optimization of exendin‐4 based agonists is described toward i) a balanced triple activity profile at the glucagon‐like peptide 1, glucagon, and gastric inhibitory polypeptide receptors for the treatment of diabetes and obesity and in parallel ii) robust physicochemical properties for 1‐daily subcutaneous application in a multiple‐dose pen device. In depth evaluation of an optimized candidate shows an excellent profile with respect to its physicochemical properties and pharmacokinetic/pharmacodynamic (PD) behavior in minipigs and monkeys.

Pharmacodynamics

Rational design

10.1002/adtp.202000052

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Citations (6)

Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multidose Formulations

Journal of Medicinal Chemistry (2018)

Andreas Evers Martin Bossart Stefania Pfeiffer‐Marek Ralf Elvert Herman Schreuder

Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 receptor agonists with regard to treatment of obesity and diabetes. We describe novel exendin-4 based dual agonists designed with an activity ratio favoring the GLP-1 versus the glucagon receptor. As result of an iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), peptide design and synthesis, experimental activity, and solubility profiling, a candidate molecule was identified. Novel SAR points are reported that allowed us to fine-tune the desired receptor activity ratio and increased solubility in the presence of antimicrobial preservatives, findings that can be of general applicability for any peptide discovery project. The peptide was evaluated in chronic in vivo studies in obese diabetic monkeys as translational model for the human situation and demonstrated favorable blood glucose and body weight lowering effects.

10.1021/acs.jmedchem.8b00292

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Citations (44)

Efficient Approximation of Ligand Rotational and Translational Entropy Changes upon Binding for Use in MM-PBSA Calculations

Journal of Chemical Information and Modeling (2016)

Ido Ben‐Shalom Stefania Pfeiffer‐Marek Karl‐Heinz Baringhaus Holger Gohlke

A major uncertainty in binding free energy estimates for protein-ligand complexes by methods such as MM-PB(GB)SA or docking scores results from neglecting or approximating changes in the configurational entropies (ΔSconfig.) of the solutes. In MM/PB(GB)SA-type calculations, ΔSconfig. has usually been estimated in the rigid rotor, harmonic oscillator approximation. Here, we present the development of a computationally efficient method (termed BEERT) to approximate ΔSconfig. in terms of the reduction in translational and rotational freedom of the ligand upon protein-ligand binding (ΔSR/T), starting from the flexible molecule approach. We test the method successfully in binding affinity computations in connection with MM-PBSA effective energies describing changes in gas-phase interactions and solvation free energies. Compared to related work by Ruvinsky and co-workers, clustering bound ligand poses based on interactions with the protein rather than structural similarity of the poses, and an appropriate averaging over single entropies associated with an individual well of the energy landscape of the protein-ligand complex, were found to be crucial. Employing three data sets of protein-ligand complexes of pharmacologically relevant targets for validation, with up to 20, in part related ligands per data set, spanning binding free energies over a range of ≤7 kcal mol-1, reliable and predictive linear models to estimate binding affinities are obtained in all three cases (R2 = 0.54-0.72, p < 0.001, root mean squared error S = 0.78-1.44 kcal mol-1; q2 = 0.34-0.67, p < 0.05, root mean squared error sPRESS = 1.07-1.36 kcal mol-1). These models are markedly improved compared to considering MM-PBSA effective energies alone, scoring functions, and combinations with ΔSconfig. estimates based on the number of rotatable bonds, rigid rotor, harmonic oscillator approximation, or interaction entropy method. As a limitation, our method currently requires a target-specific training data set to identify appropriate scaling coefficients for the MM-PBSA effective energies and BEERT ΔSR/T. Still, our results suggest that the approach is a valuable, computationally more efficient complement to existing rigorous methods for estimating changes in binding free energy across structurally (weakly) related series of ligands binding to one target.

Implicit solvation

Protein ligand

Docking (animal)

Root mean square

10.1021/acs.jcim.6b00373

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Citations (51)

Protein-Excipient Interactions Evaluated via Nuclear Magnetic Resonance Studies in Polysorbate-Based Multidose Protein Formulations: Influence on Antimicrobial Efficacy and Potential Study Approach

Journal of Pharmaceutical Sciences (2018)

Riccardo Torosantucci Britta Furtmann Bettina Elshorst Stefania Pfeiffer‐Marek Tanja Hartleb

Polysorbate

Excipient

Polyvinyl Alcohol

Ingredient

10.1016/j.xphs.2018.05.021

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Citations (14)

Rigidity Theory-Based Approximation of Vibrational Entropy Changes upon Binding to Biomolecules

Journal of Chemical Theory and Computation (2017)

Holger Gohlke Ido Ben‐Shalom Hannes Kopitz Stefania Pfeiffer‐Marek Karl‐Heinz Baringhaus

We introduce a computationally efficient approximation of vibrational entropy changes (ΔSvib) upon binding to biomolecules based on rigidity theory. From constraint network representations of the binding partners, ΔSvib is estimated from changes in the number of low frequency ("spongy") modes with respect to changes in the networks' coordination number. Compared to ΔSvib computed by normal-mode analysis (NMA), our approach yields significant and good to fair correlations for data sets of protein-protein and protein-ligand complexes. Our approach could be a valuable alternative to NMA-based ΔSvib computation in end-point (free) energy methods.

Biomolecule

Rigidity (electromagnetism)

10.1021/acs.jctc.7b00014

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Citations (19)

Long-Term Stability Prediction for Developability Assessment of Biopharmaceutics Using Advanced Kinetic Modeling

Pharmaceutics (2022)

Andreas Evers Didier Clénet Stefania Pfeiffer‐Marek

A crucial aspect of pharmaceutical development is the demonstration of long-term stability of the drug product. Biopharmaceuticals, such as proteins or peptides in liquid formulation, are typically administered via parental routes and should be stable over the shelf life, which generally includes a storing period (e.g., two years at 5 °C) and optionally an in-use period (e.g., 28 days at 30 °C). Herein, we present a case study where chemical degradation of SAR441255, a therapeutic peptide, in different formulations in combination with primary packaging materials was analyzed under accelerated conditions to derive long-term stability predictions for the recommended storing conditions (two years at 5 °C plus 28 days at 30 °C) using advanced kinetic modeling. These predictions served as a crucial decision parameter for the entry into clinical development. Comparison with analytical data measured under long-term conditions during the subsequent development phase demonstrated a high prediction accuracy. These predictions provided stability insights within weeks that would otherwise take years using measurements under long-term stability conditions only. To our knowledge, such in silico studies on stability predictions of a therapeutic peptide using accelerated chemical degradation data and advanced kinetic modeling with comparisons to subsequently measured real-life long-term stability data have not been described in literature before.

Forced degradation

Biopharmaceutics

Degradation

Chemical Stability

10.3390/pharmaceutics14020375

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Citations (18)

Peptide Optimization at the Drug Discovery-Development Interface: Tailoring of Physicochemical Properties Toward Specific Formulation Requirements

Journal of Pharmaceutical Sciences (2018)

Andreas Evers Stefania Pfeiffer‐Marek Martin Bossart Christoph Heubel Ursula Stock

10.1016/j.xphs.2018.11.043

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Citations (24)

Hot Spots and Transient Pockets: Predicting the Determinants of Small-Molecule Binding to a Protein–Protein Interface

Journal of Chemical Information and Modeling (2011)

A. Metz Christopher Pfleger Hannes Kopitz Stefania Pfeiffer‐Marek Karl‐Heinz Baringhaus

Protein-protein interfaces are considered difficult targets for small-molecule protein-protein interaction modulators (PPIMs ). Here, we present for the first time a computational strategy that simultaneously considers aspects of energetics and plasticity in the context of PPIM binding to a protein interface. The strategy aims at identifying the determinants of small-molecule binding, hot spots, and transient pockets, in a protein-protein interface in order to make use of this knowledge for predicting binding modes of and ranking PPIMs with respect to their affinity. When applied to interleukin-2 (IL-2), the computationally inexpensive constrained geometric simulation method FRODA outperforms molecular dynamics simulations in sampling hydrophobic transient pockets. We introduce the PPIAnalyzer approach for identifying transient pockets on the basis of geometrical criteria only. A sequence of docking to identified transient pockets, starting structure selection based on hot spot information, RMSD clustering and intermolecular docking energies, and MM-PBSA calculations allows one to enrich IL-2 PPIMs from a set of decoys and to discriminate between subgroups of IL-2 PPIMs with low and high affinity. Our strategy will be applicable in a prospective manner where nothing else than a protein-protein complex structure is known; hence, it can well be the first step in a structure-based endeavor to identify PPIMs.

Docking (animal)

Transient (computer programming)

10.1021/ci200322s

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Citations (124)

Solution Structure of the 30 kDa Polysulfide-Sulfur Transferase Homodimer from Wolinella succinogenes^,

Biochemistry (2004)

Yi‐Jan Lin Felician Dancea Frank Löhr Oliver Klimmek Stefania Pfeiffer‐Marek

The periplasmic polysulfide-sulfur transferase (Sud) protein encoded by Wolinella succinogenes is involved in oxidative phosphorylation with polysulfide-sulfur as a terminal electron acceptor. The polysulfide-sulfur is covalently bound to the catalytic Cys residue of the Sud protein and transferred to the active site of the membranous polysulfide reductase. The solution structure of the homodimeric Sud protein has been determined using heteronuclear multidimensional NMR techniques. The structure is based on NOE-derived distance restraints, backbone hydrogen bonds, and torsion angle restraints as well as residual dipolar coupling restraints for a refinement of the relative orientation of the monomer units. The monomer structure consists of a five-stranded parallel β-sheet enclosing a hydrophobic core, a two-stranded antiparallel β-sheet, and six α-helices. The dimer fold is stabilized by hydrophobic residues and ion pairs found in the contact area between the two monomers. Similar to rhodanese enzymes, Sud catalyzes the transfer of the polysulfide-sulfur to the artificial acceptor cyanide. Despite their similar functions and active sites, the amino acid sequences and structures of these proteins are quite different.

Polysulfide

Beta sheet

Rhodanese

10.1021/bi0356597

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Citations (22)