Hydrogen Bonding in Human P450-Substrate Interactions: A Major Contribution to Binding Affinity

The importance of hydrogen bonding, a relatively strong intermolecular force of attraction between molecules in biological systems, is discussed in the respect of P450 substrate affinity towards one or more of the human P450 enzymes that are generally associated with drug and other xenobiotic metabolism. It is shown that calculation of hydrogen bond distances and energies based on simple empirical relationships provide values that agree closely with experimental findings. It is thus possible to estimate the hydrogen bond contribution to P450 enzyme-substrate binding affinity based on modelled interactions and by use of these relatively simple formulae, particularly when employed in conjunction with substrate-lipophilicity relationships

Cytochromes P450, Oxygen, and Evolution

The role of the cytochrome P450 superfamily of heme-thiolate enzymes in oxidative metabolism is discussed in the context of evolutionary development. Concordances between the rise in atmospheric oxygen content, elaboration of the P450 phylogenetic tree and the accepted timescale for the emergence of animal phyla are described. The unique ability of the P450 monooxygenase system to activate molecular oxygen via the consecutive input of two reducing equivalents is explored, such that the possibility of oxygen radical generation and its toxic consequences can be explained in mechanistic terms, together with an appreciation of the ways in which this oxygen activating ability has been utilized by evolving biological systems in their adaptation to an increasing atmospheric oxygen concentration over the past two billon years

The Astronomical Pulse of Global Extinction Events

The linkage between astronomical cycles and the periodicity of mass extinctions is reviewed and discussed. In particular, the apparent 26 million year cycle of global extinctions may be related to the motion of the solar system around the galaxy, especially perpendicular to the galactic plane. The potential relevance of Milankovitch cycles is also explored in the light of current evidence for the possible causes of extinction events over a geological timescale

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Structural Models for Cytochrome P450�Mediated Catalysis

This review focuses on the structural models for cytochrome P450 that are improving our knowledge and understanding of the P450 catalytic cycle, and the way in which substrates bind to the enzyme leading to catalytic conversion and subsequent formation of mono-oxygenated metabolites. Various stages in the P450 reaction cycle have now been investigated using X-ray crystallography and electronic structure calculations, whereas homology modelling of mammalian P450s is currently revealing important aspects of pharmaceutical and other xenobiotic metabolism mediated by P450 involvement. These features are explored in the current review on P450-based catalysis, which emphasises the importance of structural modelling to our understanding of this enzyme's function. In addition, the results of various QSAR analyses on series of chemicals, which are metabolised via P450 enzymes, are presented such that the importance of electronic and other structural factors in explaining variations in rates of metabolism can be appreciated

Molecular Binding Interactions: Their Estimation and Rationalization in QSARs in Terms of Theoretically Derived Parameters

An extensive survey of molecular binding interactions and parameters used in QSARs is reported, which includes consideration of lipophilicity and the derivation of Linear Free Energy Relationships associated with drug-receptor binding, together with an overview of the various contributions to binding energy. The lipophilic parameter, log P, and its relevance to desolvation energy is outlined and explanation of the parameters derived from electronic structure calculation is provided, leading into a summary of molecular dynamics simulations