Multiscale methods in drug design bridge chemical and biological complexity in the search for cures

Drug action is inherently multiscale: it connects molecular interactions to emergent properties at cellular and larger scales. Simulation techniques at each of these different scales are already central to drug design and development, but methods capable of connecting across these scales will extend understanding of complex mechanisms and the ability to predict biological effects. Improved algorithms, ever-more-powerful computing architectures and the accelerating growth of rich datasets are driving advances in multiscale modeling methods capable of bridging chemical and biological complexity from the atom to the cell. Particularly exciting is the development of highly detailed, structure-based, physical simulations of biochemical systems, which are now able to access experimentally relevant timescales for large systems and, at the same time, achieve unprecedented accuracy. In this Perspective, we discuss how emerging data-rich, physics-based multiscale approaches are of the cusp of realizing long-promised impact in the discovery, design and development of novel therapeutics. We highlight emerging methods and applications in this growing field, and outline how different scales can be combined in practical modelling and simulation strategies.</p

A dormant microbial component in the development of pre-eclampsia

Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “preeclampsia” that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one