Current Topics in Medicinal Chemistry - Volume 13, Issue 18, 2013

There is a major controversy in cytochrome P450 chemistry regarding the nature of the active oxidant responsible for substrate monoxygenation. Part of this controversy originates from the fact that the later stages in the catalytic cycle of P450 enzymes proceed so fast that little experimental evidence is available. Early studies suggested an iron(IV)- oxo heme cation radical ([heme+˙)-FeIV=O] or Compound I) as the active spe Read More

In vitro validation of a protein homology model is critical for determining the predictivity of a computationally generated structure. Here we discuss the generation, validation, and application of a homology model for CYP1A1. Validation of the CYP1A1 homology model, generated using the highly homologous crystal template of human CYP1A2 (pdb 2HI4), was achieved using the prototypic substrate 7-ethoxyresorufin (Eres). The m Read More

CYP 2C8, which carries out the oxidative metabolism of at least 5% of clinical drugs, has attracted increasing attention in recent years. New drugs (substances), inducers and inhibitors of CYP 2C8 have been developed and the drug metabolism has been investigated to understand the clinical role of CYP2C8. The cases of CYP2C8 genetic polymorphisms linked to diseases have increased and have been investigated. Herein, imp Read More

Engineered biocatalysts offer the opportunity to introduce modifications into complex lead molecules and drug candidates in a chemo-, regio- and stereoselective manner that is difficult to accomplish using traditional synthetic organic chemistry. As candidate biocatalysts, the cytochrome P450 enzymes that metabolize drugs and other xenobiotics are amongst the most versatile agents known. Not only can they mediate an exce Read More

Stroke is a devastating disease associated with high morbidity and mortality. Despite the approved indication of systemic thrombolytic therapy in the United States for the acute management of ischemic stroke, its use is limited given a strict eligibility criteria and a risk for hemorrhagic transformation as a feared adverse effect. Many agents have been studied without success for neuroprotection in patients with stroke t Read More

Emergence of new and medically resistant pathogenic microbes continues to escalate toward worldwide public health, wild habitat, and commercial crop and livestock catastrophes. Attempts at solving this problem with sophisticated modern biotechnologies, such as smart vaccines and microbicidal and microbistatic drugs that precisely target parasitic bacteria, fungi, and protozoa, remain promising without major cli Read More

Alzheimer's disease (AD) is the most common cause of dementia and a major cause of morbidity and mortality. The greatest risk factor for AD is age and as many countries are experiencing an aging population, the expected rise in AD threatens to have serious medical and socioeconomic impact in the coming decades. The only approved medications for AD are symptomatic and there are no currently available disease mo Read More

The process of discovering a pharmacological compound that elicits a desired clinical effect with minimal side effects is a challenge. Prior to the advent of high-performance computing and large-scale screening technologies, drug discovery was largely a serendipitous endeavor, as in the case of thalidomide for erythema nodosum leprosum or cancer drugs in general derived from flora located in far-reaching geographic locatio Read More

Movement disorders are a heterogeneous group of both common and rare neurological conditions characterized by abnormalities of motor functions and movement patterns. This work overviews recent successes and ongoing studies of repositioning relating to this disease group, which underscores the challenge of integrating the voluminous and heterogeneous findings required for making suitable drug repositioning de Read More

Characteristic symptoms of schizophrenia and bipolar disorders have been described and classified about a century ago. Each of these disorders may cause considerable impairment reflecting substantial alterations in cognition, perception, and mood. Though both disease concepts are well established, psychopharmacological treatment strategies, involving first- and second-generation antipsychotics, benzodiazepines and m Read More

Drug repurposing (drug repositioning, drug reprofiling, drug retasking) gains increasing importance as the development of new drugs becomes increasingly expensive. Though only a few compounds have been approved for new indications in the field of metabolic disorders, there are a number of substances which have the potential to become reprofiled in a new indication. Generally, reprofiled drugs for metabolic disor Read More