Quantitative Structure-function Relationships Research Articles

Machine learning in drug delivery

For decades, drug delivery scientists have been performing trial-and-error experimentation to manually sample parameter spaces and optimize release profiles through rational design. To enable this approach, scientists spend much of their career learning nuanced drug-material interactions that drive system behavior. In relatively simple systems, rational design criteria allow us to fine tune release profiles and enable efficacious therapies. However, as materials and drugs become increasingly sophisticated and their interactions have non-linear and compounding effects, the field is suffering the Curse of Dimensionality which prevents us from comprehending complex structure-function relationships. In the past, we have embraced this complexity by implementing high-throughput screens to increase the probability of finding ideal compositions. However, this brute force method was inefficient and led many to abandon these fishing expeditions. Fortunately, methods in data science including artificial intelligence / machine learning (AI/ML) are providing ideal analytical tools to model this complex data and ascertain quantitative structure-function relationships. In this Oration, I speak to the potential value of data science in drug delivery with particular focus on polymeric delivery systems. Here, I do not suggest that AI/ML will simply replace mechanistic understanding of complex systems. Rather, I propose that AI/ML should be yet another useful tool in the lab to navigate complex parameter spaces. The recent hype around AI/ML is breathtaking and potentially over inflated, but the value of these methods is poised to revolutionize how we perform science. Therefore, I encourage readers to consider adopting these skills and applying data science methods to their own problems. If done successfully, I believe we will all realize a paradigm shift in our approach to drug delivery.

Establishing Quantifiable Guidelines for Antimicrobial α/β-Peptide Design: A Partial Least-Squares Approach to Improve Antimicrobial Activity and Reduce Mammalian Cell Toxicity.

Antimicrobial peptides (AMPs) are promising candidates to combat pathogens that are resistant to conventional antimicrobial drugs because they operate through mechanisms that involve membrane disruption. However, the use of AMPs in clinical settings has been limited, at least in part, by their susceptibility to proteolytic degradation and their lack of selectivity toward pathogenic microbes vs mammalian cells. We recently reported on the design of α- and β-peptide oligomers structurally templated upon the naturally occurring α-helical AMP aurein 1.2. These α/β-peptide oligomers are more proteolytically stable than aurein 1.2 and have several other attributes that render them attractive as alternatives to conventional AMPs. This study describes the influence of peptide physicochemical properties on the broad-spectrum activity of aurein 1.2-based α/β-peptide mimics against nine bacterial, fungal, and mammalian cell lines. We used a partial least-squares regression (PLSR)-supervised machine learning model to quantify and visualize relationships between experimentally determined physicochemical properties (e.g., hydrophobicity, charge, and helicity) and experimentally measured cell-type-specific activities of 21 peptides in a 149-member α/β-peptide library. Using this approach, we identified several peptides that were predicted to exhibit enhanced broad-spectrum selectivity, a measure that evaluates antimicrobial activity relative to mammalian cell toxicity compared to aurein 1.2. Experimental validation demonstrated high model predictive performance, and characterization of compounds with the highest broad-spectrum selectivity revealed peptide hydrophobicity, helicity, and helical rigidity to be strong predictors of broad-spectrum selectivity. The most selective peptide identified from the model prediction has more than a 13-fold improvement in broad-spectrum selectivity than that of aurein 1.2, demonstrating the ability of using PLSR models to identify quantitative structure-function relationships for nonstandard amino acid-containing peptides. Overall, this work establishes quantifiable guidelines for the rational design of helical antimicrobial α/β-peptides and identifies promising new α/β-peptides with significantly reduced mammalian toxicities and improved antifungal and antibacterial activities relative to aurein 1.2.

A DNA Cleavage Assay Using Synthetic Oligonucleotide Containing a Single Site-Directed Lesion for In Vitro Base Excision Repair Study.

Many chemicals cause mutation or cancer in animals and humans by forming DNA lesions, including base adducts, which play a critical role in mutagenesis and carcinogenesis. A large number of such adducts are repaired by the DNA glycosylase-mediated base excision repair (BER) pathway, and some are processed by nucleotide excision repair (NER) and nucleotide incision repair (NIR). To understand what structural features determine repair enzyme specificity and mechanism in chemically modified DNA in vitro, we developed and optimized a DNA cleavage assay using defined oligonucleotides containing a single, site specifically placed lesion. This assay can be used to investigate novel activities against any newly identified derivatives from chemical compounds, substrate specificity and cleavage efficiency of repair enzymes, and quantitative structure-function relationships. Overall, the methodology is highly sensitive and can also be modified to explore whether a lesion is processed by NER or NIR activity, as well as to study its miscoding properties in translesion DNA synthesis (TLS).

Transferrable selectivity profiles enable prediction in synergistic catalyst space.

Organometallic intermediates participate in many multi-catalytic enantioselective transformations directed by a chiral catalyst, but the requirement of optimizing two catalyst components is a significant barrier to widely adopting this approach for chiral molecule synthesis. Algorithms can potentially accelerate the screening process by developing quantitative structure-function relationships from large experimental datasets. However, the chemical data available in this catalyst space is limited. Herein, we report a data-driven strategy that effectively translates selectivity relationships trained on enantioselectivity outcomes derived from one catalyst reaction systems where an abundance of data exists, to synergistic catalyst space. We describe three case studies involving different modes of catalysis (Brønsted acid, chiral anion, and secondary amine) that substantiate the prospect of this approach to predict and elucidate selectivity in reactions where more than one catalyst is involved. Ultimately, the success in applying our approach to diverse areas of asymmetric catalysis implies that this general workflow should find broad use in the study and development of new enantioselective, multi-catalytic processes.

Contribution of facet joints, axial compression, and composition to human lumbar disc torsion mechanics.

Stresses applied to the spinal column are distributed between the intervertebral disc and facet joints. Structural and compositional changes alter stress distributions within the disc and between the disc and facet joints. These changes influence the mechanical properties of the disc joint, including its stiffness, range of motion, and energy absorption under quasi-static and dynamic loads. There have been few studies evaluating the role of facet joints in torsion. Furthermore, the relationship between biochemical composition and torsion mechanics is not well understood. Therefore, the first objective of this study was to investigate the role of facet joints in torsion mechanics of healthy and degenerated human lumbar discs under a wide range of compressive preloads. To achieve this, each disc was tested under four different compressive preloads (300-1200 N) with and without facet joints. The second objective was to develop a quantitative structure-function relationship between tissue composition and torsion mechanics. Facet joints have a significant contribution to disc torsional stiffness (∼60%) and viscoelasticity, regardless of the magnitude of axial compression. The findings from this study demonstrate that annulus fibrosus GAG content plays an important role in disc torsion mechanics. A decrease in GAG content with degeneration reduced torsion mechanics by more than an order of magnitude, while collagen content did not significantly influence disc torsion mechanics. The biochemical-mechanical and compression-torsion relationships reported in this study allow for better comparison between studies that use discs of varying levels of degeneration or testing protocols and provide important design criteria for biological repair strategies. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Molecular basis of substrate translocation through the outer membrane channel OprD of Pseudomonas aeruginosa.

The objective of this study is to identify the structural features governing the transport of molecules through nanometric channel proteins at a molecular level. Our focus is to come up with a precise understanding of the structure and dynamics of the outer membrane porin OprD of the Gram-negative bacterium Pseudomonas aeruginosa by studying the translocation of natural amino acid residues/substrates through it. We used in silico electrophysiology and metadynamics simulation techniques as they can provide precise information on the molecule/channel interactions at the atomic scale that allows testing quantitative structure-function relationships. We performed our simulations on the whole OprD protein, with all loops modelled and without any constraints to keep the channel open. Dynamics of both internal and external loops and the polar nature of the eyelet region play important roles in modulating the translocation of molecules through OprD by creating two alternative paths for translocation. All positive residues take the main path upon binding in the negative pocket just above the constriction region. The same factor is unfavourable for negative substrates and hence they have a relatively high barrier for translocation. Differently, neutral substrates do not show any specificity and they can follow the two alternative paths.

Antimicrobial Photodynamic Therapy with Functionalized Fullerenes: Quantitative Structure-activity Relationships

Photosensitive dyes or photo sensitizers (PS) in combination with visible light and oxygen produce reactive oxygen species that kill cells in the process known as photodynamic therapy (PDT). Antimicrobial PDT employs PS that is selective for microbial cells and is a new treatment for infections. Most antimicrobial PS is based on tetrapyrrole or phenothiazinium structures that have been synthesized to carry quaternary cationic charges or basic amino groups. However we recently showed that cationic-substituted fullerene derivative were highly effective in killing a broad spectrum of microbial cells after illumination with white light. In the present report we compared a new group of synthetic fullerene derivatives that possessed either basic or quaternary amino groups as antimicrobial PS against Gram-positive (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli) and fungi (Candida albicans). Quantitative structure-function relationships were derived with LogP and hydrophilic lipophilic balance parameters. Compounds with non-quaternary amino groups tended to form nanoaggregates in water and were only effective against S. aureus. The most important determinant of effectiveness was an increased number of quaternary cationic groups that were widely dispersed around the fullerene cage to minimize aggregation. S. aureus was most susceptible; E. coli was intermediate, while C. albicans was the most resistant species tested. The high effectiveness of antimicrobial PDT with quaternized fullerenes suggest they may have applications in treatment of superficial infections (for instance in wounds and burns) where light penetration into tissue is not problematic.

Foldable structures and the natural design of pollen grains

Upon release from the anther, pollen grains of angiosperm flowers are exposed to a dry environment and dehydrate. To survive this process, pollen grains possess a variety of physiological and structural adaptations. Perhaps the most striking of these adaptations is the ability of the pollen wall to fold onto itself to prevent further desiccation. Roger P. Wodehouse coined the term harmomegathy for this folding process in recognition of the critical role it plays in the survival of the pollen grain. There is still, however, no quantitative theory that explains how the structure of the pollen wall contributes to harmomegathy. Here we demonstrate that simple geometrical and mechanical principles explain how wall structure guides pollen grains toward distinct folding pathways. We found that the presence of axially elongated apertures of high compliance is critical for achieving a predictable and reversible folding pattern. Moreover, the intricate sculpturing of the wall assists pollen closure by preventing mirror buckling of the surface. These results constitute quantitative structure-function relationships for pollen harmomegathy and provide a framework to elucidate the functional significance of the very diverse pollen morphologies observed in angiosperms.

Innovative cationic fullerenes as broad-spectrum light-activated antimicrobials

Photodynamic inactivation is a rapidly developing antimicrobial technology that combines a nontoxic photoactivatable dye or photosensitizer in combination with harmless visible light of the correct wavelength to excite the dye to its reactive-triplet state that will then generate reactive oxygen species that are highly toxic to cells. Buckminsterfullerenes are closed-cage molecules entirely composed of sp2-hybridized carbon atoms, and although their main absorption is in the UV, they also absorb visible light and have a long-lived triplet state. When C 60 fullerene is derivatized with cationic functional groups it forms molecules that are more water-soluble and can mediate photodynamic therapy efficiently upon illumination; moreover, cationic fullerenes can selectively bind to microbial cells. In this report we describe the synthesis and characterization of several new cationic fullerenes. Their relative effectiveness as broad-spectrum antimicrobial photosensitizers against gram-positive and gram-negative bacteria, and a fungal yeast was determined by quantitative structure-function relationships. From the Clinical Editor Photodynamic inactivation (PDI) is a rapidly developing antimicrobial technology in which a non-toxic photoactivatable dye or photosensitizer is excited with harmless visible light to its reactive state, where it will generate highly toxic reactive oxygen species. Buckminsterfullerenes derivatized with cationic functional groups form molecules that are water-soluble and mediate PDI efficiently. These fullerenes can also selectively bind to microbial cells. Several new cationic fullerenes are presented in this paper, and their efficacy against Gram-positive, Gram-negative bacteria, and a fungal yeast is also demonstrated.

Conformation-Specific Recognition of Carcinogen−DNA Adduct in Escherichia coli Nucleotide Excision Repair

We report a systematic and quantitative structure-function relationship study of the major N-[deoxyguanosin-8-yl]-2-aminofluorene adduct (AF) derived from the prototype carcinogen 2-aminofluorene and its derivatives. The AF adduct is known to exist in two distinct conformational motifs, depending upon the location of the hydrophobic fluorine moiety: major groove binding "B type" (B) conformation (AF-dGanti) and base-displaced "stacked" (S) conformation (AF-dGsyn). The AF-induced S/B conformational heterogeneity is sequence-dependent and follows a typical two-site dynamic chemical exchange. The population of S conformation decreases in the order of 3'-G > A > C > T, indicating the importance of the purine flanking bases in promoting the stacking structure. Line-shape analysis showed that the S/B interconversion energy barriers (DeltaG) are in the narrow 14-16 kcal/mol range. The energy differences of the two conformers are relatively small (<0.5 kcal/mol), suggesting a possibility for a facile adduct conformation switch in the active site of a polymerase. The S/B equilibrium modulates the efficiency of Escherichia coli UvrABC-based nucleotide excision repair (NER) in a conformation-specific manner. The 19F NMR/NER results indicate greater repair susceptibility for the base-displaced S conformer, which lacks a Watson-Crick base pair at the lesion site. These findings represent the first of its kind quantitative structure-function work relating NER activity to a specific adduct conformer and will lead to a better understanding of how bulky DNA adducts are accommodated by the repair protein.

Visual Field Defects and Retinal Ganglion Cell Losses in Patients With Glaucoma

To determine whether the structure-function relationships for glaucoma in humans and experimental glaucoma in monkeys are similar. The study was based on retinal ganglion cell density and visual thresholds in patients with documented glaucoma. Data were analyzed with a model that predicted ganglion cell density from standard clinical perimetry, which was then compared with histologic cell counts. The model, without free parameters, produced accurate and relatively precise quantification of ganglion cell density associated with visual field defects. For 437 sets of data, the unity correlation for predicted vs measured cell density had a coefficient of determination of 0.39. The mean absolute deviation of the predicted vs measured values was 2.59 decibels (dB), and the mean +/- SD of the distribution of residual errors of prediction was -0.26 +/- 3.22 dB. Visual field defects based on standard clinical perimetry are proportional to neural losses caused by glaucoma. The evidence for quantitative structure-function relationships provides a scientific basis for interpreting glaucomatous neuropathy from visual thresholds and supports the application of standard perimetry to establish the stage of the disease.

Supermolecular Control of Charge Transfer in Dye‐Sensitized Nanocrystalline TiO2 Films: Towards a Quantitative Structure–Function Relationship

Supermolecular Control of Charge Transfer in Dye‐Sensitized Nanocrystalline TiO₂ Films: Towards a Quantitative Structure–Function Relationship

Supermolecular Control of Charge Transfer in Dye‐Sensitized Nanocrystalline TiO2 Films: Towards a Quantitative Structure–Function Relationship

Trennung auf Zeit: In einem Farbstoff-sensibilisierten nanokristallinen TiO2-Film (siehe Schema) kann ein bemerkenswert langlebiger (4 s) ladungsgetrennter Zustand erzeugt werden. Als Schlüsselparameter für die Steuerung des Ladungstransfers an der Farbstoff/TiO2-Grenzfläche erwies sich der Abstand zwischen dem Kationenzentrum des Farbstoffs und der Elektrodenoberfläche. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2005/z500363_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Quantitative structure-function and structure-stability relationships of purposely modified proteins.

Quantitative structure-function relationships (QSFR) and quantitative structure-stability relationships (QSSR) analyses are described here. The objective of these analyses is to investigate and quantitatively describe the effect of the changes in structure of protein on its function or stability. During the analysis, the structural and physico-chemical properties of the amino acid residues are related to activity or stability data derived for the group of proteins containing systematic substitutions at certain positions. Four examples of the application of these analyses on the data obtained with proteins modified by site-directed mutagenesis experiments are provided. Structure-function relationships were studied for 15 mutants in position 172 of the haloalkane dehalogenase and 19 mutants in position 222 of the subtilisin, while the structure-stability relationships were investigated for 13 mutants in position 157 of phage T4 lysozyme and 18 mutants in position 49 of alpha-subunits tryptophan synthase. A total of 402 molecular descriptors derived from AAindex database were used to quantify amino acid properties and the multivariate statistical technique--partial least squares projections to latent structures--was used to identify those of them which are important for explanation of the activity and stability data. Quantitative models were developed and internally validated for every data set. The possibilities for further development of both analyses and their application for predictive and analytical purposes in protein engineering research are discussed.

Quantitative Structure‐Function Relationships of the Single‐Point Mutants of Haloalkane Dehalogenase: A Multivariate Approach

AbstractThe applicability of multivariate statistical methods for the systematic analysis of results from the site‐directed experiments was tested. Dehalogenation data obtained with 15 single‐point mutants of haloalkane dehalogenase of Xanthobacter autotrophicus GJ10 has been related to various physico‐chemical properties of substituted amino acids. A two component model which explains 84% of activity data was derived. The most influential properties, required on position 172 in haloalkane dehalogenase were: aromaticity, main‐chain flexibility, refractivity and bulkiness, and were related mainly to the transition state/halide stabilization. The general usage of multivariate techniques for quantitative structure‐function relationships (QSFR) and protein engineering studies can be recommended. Score and loading plots from Principal Component Analysis (PCA) of physico‐chemical properties of amino acids can be used for planning and design of site‐directed mutagenesis experiments, while the models obtained from Projection to Latent Structures (PLS) can provide predictions on the effect of the mutations on protein functionality prior to its testing.

Rational Design of Conformationally Flexible Drugs

Synopsis The rational design of conformationally flexible drugs is briefly reviewed and conformational flexibility is identified as a major stumbling block in the application of QSAR-type methods. With a worked example for thyroid stimulating hormone releasing factor (TRH) and analogues, an approach with several new features is described which leads to quantitative structure-function relationships for the analogues studied so far. With the advantage of hindsight, it appears that with proper treatment good structure-activity relationships might be expected even in the usual case of a receptor of unknown structure, and the reasons for this are described.