Investigation of local soil resistance on suction caissons at capacity in undrained clay under combined loading

Winkler modelling offers a flexible and computationally efficient framework for estimating suction caisson capacity. However, there is a limited understanding of the local soil resistance acting on caissons at capacity under combined six degrees-of-freedom (6DoF) loading, which is essential for accurately estimating caisson failure envelopes. Furthermore, existing simplified design models for caissons cannot assess capacity under non-planar lateral and moment loading, which is common in offshore wind applications. To address these limitations, this paper presents a comprehensive three-dimensional (3D) finite element analysis (FEA) study, which investigates the local soil resistance acting on the caisson at capacity in undrained clay under combined 6DoF loading. The paper introduces the concept of ‘soil reaction failure envelopes’ to characterise the interactions between soil reactions at capacity. Closed-form formulations are derived to approximate these soil reaction failure envelopes. An elastoplastic Winkler model is then developed, incorporating linear elastic perfectly plastic soil reactions based on these formulations. The results demonstrate that the Winkler model can provide efficient and reasonably accurate estimations of caisson capacity under combined 6DoF loading, even for irregular soil profiles that pose much uncertainty and challenges to existing macro-element models

A systematic framework for formulating convex failure envelopes in multiple loading dimensions

The failure envelope approach is widely used to assess the ultimate capacity of shallow foundations for combined loading, and to develop foundation macro-element models. Failure envelopes are typically determined by fitting appropriate functions to a set of discrete failure load data, determined either experimentally or numerically. However, current procedures to formulate failure envelopes tend to be ad hoc, and the resulting failure envelopes may not have the desirable features of being convex and well-behaved for the entire domain of interest. This paper describes a new systematic framework to determine failure envelopes – based on the use of sum of squares convex polynomials – that are guaranteed to be convex and well-behaved. The framework is demonstrated by applying it to three data sets for failure load combinations (vertical load, horizontal load and moment) for shallow foundations on clay. An example foundation macro-element model based on the proposed framework is also described

Assessment of numerical procedures for determining shallow foundation failure envelopes

The failure envelope approach is commonly used to assess the capacity of shallow foundations under combined loading, but there is limited published work that compares the performance of various numerical procedures for determining failure envelopes. This paper addresses this issue by carrying out a detailed numerical study to evaluate the accuracy, computational efficiency and resolution of these numerical procedures. The procedures evaluated are the displacement probe test, the load probe test, the swipe test (referred to in this paper as the single swipe test) and a less widely used procedure called the sequential swipe test. Each procedure is used to determine failure envelopes for a circular surface foundation and a circular suction caisson foundation under planar vertical, horizontal and moment (VHM) loading for a linear elastic, perfectly plastic von Mises soil. The calculations use conventional, incremental-iterative finite-element analysis (FEA) except for the load probe tests, which are performed using finite-element limit analysis (FELA). The results demonstrate that the procedures are similarly accurate, except for the single swipe test, which gives a load path that under-predicts the failure envelope in many of the examples considered. For determining a complete VHM failure envelope, the FEA-based sequential swipe test is shown to be more efficient and to provide better resolution than the displacement probe test, while the FELA-based load probe test is found to offer a good balance of efficiency and accuracy

Investigation of local soil resistance on suction caissons at capacity in undrained clay under combined loading

Winkler modelling offers a flexible and computationally efficient framework for estimating suction caisson capacity. However, there is a limited understanding of the local soil resistance acting on caissons at capacity under combined six degrees-of-freedom (6DoF) loading, which is essential for accurately estimating caisson failure envelopes. Furthermore, existing simplified design models for caissons cannot assess capacity under non-planar lateral and moment loading, which is common in offshore wind applications. To address these limitations, this paper presents a comprehensive three-dimensional (3D) finite element analysis (FEA) study, which investigates the local soil resistance acting on the caisson at capacity in undrained clay under combined 6DoF loading. The paper introduces the concept of ‘soil reaction failure envelopes’ to characterise the interactions between soil reactions at capacity. Closed-form formulations are derived to approximate these soil reaction failure envelopes. An elastoplastic Winkler model is then developed, incorporating linear elastic perfectly plastic soil reactions based on these formulations. The results demonstrate that the Winkler model can provide efficient and reasonably accurate estimations of caisson capacity under combined 6DoF loading, even for irregular soil profiles that pose much uncertainty and challenges to existing macro-element models

Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharma- cology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R

Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R

Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

Partial agonists of the dopamine D2 receptor (D2R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis, analytical pharmacology, ligand fragments and molecular dynamics simulations to identify the D2R-aripiprazole interactions that contribute to affinity and efficacy. We reveal that an interaction between the secondary pharmacophore of aripiprazole and a secondary binding pocket defined by residues at the extracellular portions of transmembrane segments 1, 2 and 7 determine the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism through which to fine-tune the intrinsic efficacy of D2R agonists

The role of kinetic context in apparent biased agonism at GPCRs

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that ‘kinetic context’, as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism

Analyzing GPCR-Ligand Interactions with the Fragment Molecular Orbital (FMO) Method

G-protein-coupled receptors (GPCRs) have enormous physiological and biomedical importance, and therefore it is not surprising that they are the targets of many prescribed drugs. Further progress in GPCR drug discovery is highly dependent on the availability of protein structural information. However, the ability of X-ray crystallography to guide the drug discovery process for GPCR targets is limited by the availability of accurate tools to explore receptor-ligand interactions. Visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum mechanics (QM) approaches are often too computationally expensive to be of practical use in time-sensitive situations, but the fragment molecular orbital (FMO) method offers an excellent solution that combines accuracy, speed, and the ability to reveal key interactions that would otherwise be hard to detect. Integration of GPCR crystallography or homology modelling with FMO reveals atomistic details of the individual contributions of each residue and water molecule toward ligand binding, including an analysis of their chemical nature. Such information is essential for an efficient structure-based drug design (SBDD) process. In this chapter, we describe how to use FMO in the characterization of GPCR-ligand interactions