Model-based Target Pharmacology Assessment (mTPA): An Approach Using PBPK/PD Modeling and Machine Learning to Design Medicinal Chemistry and DMPK Strategies in Early Drug Discovery.

The optimal pharmacokinetic (PK) required for a drug candidate to elicit efficacy is highly dependent on the targeted pharmacology, a relationship that is often not well characterized during early phases of drug discovery. Generic assumptions around PK and potency risk misguiding screening and compound design toward nonoptimal absorption, distribution, metabolism, and excretion (ADME) or molecular properties and ultimately may increase attrition as well as hit-to-lead and lead optimization timelines. The present work introduces model-based target pharmacology assessment (mTPA), a computational approach combining physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling, sensitivity analysis, and machine learning (ML) to elucidate the optimal combination of PK, potency, and ADME specific for the targeted pharmacology. Examples using frequently encountered PK/PD relationships are presented to illustrate its application, and the utility and benefits of deploying such an approach to guide early discovery efforts are discussed.

mol2sphere: spherical decomposition of multi-domain molecules for visualization and coarse grained spatial modeling.

Motivation: Proteins, especially those involved in signaling pathways are composed of functional modules connected by linker domains with varying degrees of flexibility. To understand the structure-function relationships in these macromolecules, it is helpful to visualize the geometric arrangement of domains. Furthermore, accurate spatial representation of domain structure is necessary for coarse-grain models of the multi-molecular interactions that comprise signaling pathways. Results: We introduce a new tool, mol2sphere, that transforms the atomistic structure of a macromolecule into a series of linked spheres corresponding to domains. It does this with a k-means clustering algorithm. It may be used for visualization or for coarse grain modeling and simulation. Availability and implementation: PyMOL plugin, source, and documentation.https://nmrbox.org/registry/mol2sphere. SpringSaLaD executables and documentation: http://vcell.org/ssalad, SpringSaLaD v.2 source: https://github.com/jmasison/SpringSaLaD.

A Bayesian Framework for Generalized Linear Mixed Modeling Identifies New Candidate Loci for Late-Onset Alzheimer's Disease.

Recent technical and methodological advances have greatly enhanced genome-wide association studies (GWAS). The advent of low-cost, whole-genome sequencing facilitates high-resolution variant identification, and the development of linear mixed models (LMM) allows improved identification of putatively causal variants. While essential for correcting false positive associations due to sample relatedness and population stratification, LMMs have commonly been restricted to quantitative variables. However, phenotypic traits in association studies are often categorical, coded as binary case-control or ordered variables describing disease stages. To address these issues, we have devised a method for genomic association studies that implements a generalized LMM (GLMM) in a Bayesian framework, called Bayes-GLMM Bayes-GLMM has four major features: (1) support of categorical, binary, and quantitative variables; (2) cohesive integration of previous GWAS results for related traits; (3) correction for sample relatedness by mixed modeling; and (4) model estimation by both Markov chain Monte Carlo sampling and maximal likelihood estimation. We applied Bayes-GLMM to the whole-genome sequencing cohort of the Alzheimer's Disease Sequencing Project. This study contains 570 individuals from 111 families, each with Alzheimer's disease diagnosed at one of four confidence levels. Using Bayes-GLMM we identified four variants in three loci significantly associated with Alzheimer's disease. Two variants, rs140233081 and rs149372995, lie between PRKAR1B and PDGFA The coded proteins are localized to the glial-vascular unit, and PDGFA transcript levels are associated with Alzheimer's disease-related neuropathology. In summary, this work provides implementation of a flexible, generalized mixed-model approach in a Bayesian framework for association studies.

3D-GNOME: an integrated web service for structural modeling of the 3D genome.

Recent advances in high-throughput chromosome conformation capture (3C) technology, such as Hi-C and ChIA-PET, have demonstrated the importance of 3D genome organization in development, cell differentiation and transcriptional regulation. There is now a widespread need for computational tools to generate and analyze 3D structural models from 3C data. Here we introduce our 3D GeNOme Modeling Engine (3D-GNOME), a web service which generates 3D structures from 3C data and provides tools to visually inspect and annotate the resulting structures, in addition to a variety of statistical plots and heatmaps which characterize the selected genomic region. Users submit a bedpe (paired-end BED format) file containing the locations and strengths of long range contact points, and 3D-GNOME simulates the structure and provides a convenient user interface for further analysis. Alternatively, a user may generate structures using published ChIA-PET data for the GM12878 cell line by simply specifying a genomic region of interest. 3D-GNOME is freely available at http://3dgnome.cent.uw.edu.pl/.

SpringSaLaD: A Spatial, Particle-Based Biochemical Simulation Platform with Excluded Volume.

We introduce Springs, Sites, and Langevin Dynamics (SpringSaLaD), a comprehensive software platform for spatial, stochastic, particle-based modeling of biochemical systems. SpringSaLaD models biomolecules in a coarse-grained manner as a group of linked spherical sites with excluded volume. This mesoscopic approach bridges the gap between highly detailed molecular dynamics simulations and the various methods used to study network kinetics and diffusion at the cellular level. SpringSaLaD is a standalone tool that supports model building, simulation, visualization, and data analysis, all through a user-friendly graphical user interface that should make it more accessible than tools built into more comprehensive molecular dynamics infrastructures. Importantly, for bimolecular reactions we derive an exact expression relating the macroscopic on-rate to the various microscopic parameters with the inclusion of excluded volume; this makes SpringSaLaD more accurate than other tools, which rely on approximate relationships between these parameters.

Stoichiometry of Nck-dependent actin polymerization in living cells.

Regulation of actin dynamics through the Nck/N-WASp (neural Wiskott-Aldrich syndrome protein)/Arp2/3 pathway is essential for organogenesis, cell invasiveness, and pathogen infection. Although many of the proteins involved in this pathway are known, the detailed mechanism by which it functions remains undetermined. To examine the signaling mechanism, we used a two-pronged strategy involving computational modeling and quantitative experimentation. We developed predictions for Nck-dependent actin polymerization using the Virtual Cell software system. In addition, we used antibody-induced aggregation of membrane-targeted Nck SH3 domains to test these predictions and to determine how the number of molecules in Nck aggregates and the density of aggregates affected localized actin polymerization in living cells. Our results indicate that the density of Nck molecules in aggregates is a critical determinant of actin polymerization. Furthermore, results from both computational simulations and experimentation support a model in which the Nck/N-WASp/Arp2/3 stoichiometry is 4:2:1. These results provide new insight into activities involving localized actin polymerization, including tumor cell invasion, microbial pathogenesis, and T cell activation.

General mechanism of actomyosin contractility.

Stress generation by myosin minifilaments is analyzed via simulation of their motion in a random actin network. The stresses are overwhelmingly contractile because minifilament equilibrium positions having contractile stress have lower energy than those for expansive stress. Force chains lead to unexpectedly large stresses.