Inhibitor search

Rummey et al. [223] searched replacements for the pyrrolidine present in their DPP-IV inhibitor searching a 10,000-molecule subset of small primary aliphatic amines extracted from the available chemical directory and visually inspected the top 500 of them. Four were selected for testing and two of them were novel hits. 

Many new interest boxes have been added that relate organic chemistry to biology and medicine. Some examples Breast Cancer and Aromatase Inhibitors, Searching for Drugs An Antihistamine, a Nonsedating Antihistamine, and a Drug for Ulcers Diseases Caused by a Misfolded Protein How Tamiflu Works Three Different Antibiotics Act by a Common Mechanism. 

Zhang and co-workers worked on the structure-based, computer-assisted search for low molecular weight, non-peptidic protein tyrosine phosphate IB (PTPIB) inhibitors, also using the DOCK methodology [89], They identified several potent and selective PTPIB inhibitors by saeening the ACD. 

Aristeromycin. Aristeromycin (36), the first carbocyhc analogue of adenosine, was isolated from the culture filtrates of S. citricolor as part of a search for inhibitors of bacterial leaf blight (1—4). A herbicidaHy active hypoxanthine analogue of (36), coaristeromycin, has also been isolated (108). Several chemical syntheses of (36) have appeared (1—4,109). It inhibits Aanthomonas OTjc e and Eyricularia bacterial leaf blight, blast disease of rice plants, and... 

Computer-aided inhibitor design is a relatively new and powerful approach for the development of novel, potentially potent, nonsubstrate-analogue enzyme inhibitors. Computer-aided methods and biological screening can each lead to new classes of novel inhibitors. However, computer-aided design methods can focus the search for inhibitors, thereby circumventing much of the time-consuming synthetic and natural product purification procedures for those compounds they find unlikely to function as inhibitors. 

DOCK search of enzyme-inhibitor active site as described in text. 

A final but important consideration is viral mutation. Certain mutant HIV strains are resistant to one or more of the protease inhibitors, and even for patients who respond initially to protease inhibitors it is possible that mutant viral forms may eventually thrive in the infected individual. The search for new and more effective protease inhibitors is ongoing. 

Today, 3D databases, which provide the means for storing and searching for 3D information of compounds, are proven to be useful tools in drug discovery programs. This is well exemplified with the recent discovery of novel nonpeptide HIV-1 protease inhibitors using pharmacophore searches of the National Cancer Institute 3D structural database [13-15]. 

A difficulty arises in describing the precise chemical nature of many inhibitor formulations that are actually used in practice. With the advancing technology of inhibitor applications there are an increasing number of formulations that are marketed under trade names. The compositions of these are, for various reasons, frequently not disclosed. A similar problem arises in describing the composition of many inhibitor formulations used in the former Soviet Union. Here the practice is to use an abbreviated classification system and it is often difficult to trace the actual composition, although in many cases a judicious literature search will provide the required information. 

The search for inhibitors of this pathway began with the first key regulatory enzyme, HMG CoA reductase. Several clinically useful inhibitors of HMG CoA reductase are now known. One of the most successful, Mevacor, produced by Merck, is one of the pharmaceutical industry s best selling products. However, the problem with inhibiting a branched biosynthetic pathway at an early point is that the biosynthesis of other crucial biomolecules may also be inhibited. Indeed, there is some evidence that levels of ubiquinone and the dolichols are affected by some HMG CoA reductase inhibitors. Consequently, efforts have recently been directed towards finding inhibitors of squalene synthase, the enzyme controlling the first step on the route to cholesterol after the FPP branch point. 

These modified Rosenmund von Braun reaction conditions were also used by Gopalsamy et al. for the rapid cyanation of the 1,3,4,9-tetrahydropyrano-[3,4-fc]indole skeleton while searching for potent and selective Hepatitis C virus polymerase inhibitors (Scheme 74) [84]. 

The initial search for an inhibitor of the SARS 3CL protease focused on preexisting drugs and compounds, some tested empirically and others selected based on modeling. The HlV-1 PI nelfinavir and lopinavir/ritonavir have been considered, with the latter actually used clinically in SARS CoV-infected subjects. The rhi-novirus inhibitor ruprintrivir and related compounds have also been tested (reviewed in Fear et al. 2007). However, in the absence of any elements of specificity, these preexisting compounds would be expected to have low potency. 

It is important to recognize that different types of inhibitors often function by different mechanisms, and that a given antioxidant may react in more than one way. Thus, a material that acts as an antioxidant under one set of conditions may become a pro-oxidant in another simation. The search for possible synergistic combinations of antioxidants can be conducted more logically and efficiently if we seek to combine the effects of different modes of action. Five general modes of oxidation inhibition are commonly recognized ... 

AmpC P-Lactamase. A map of hot spots was constructed from the X-ray structure of AmpC P-lactamase and a university version of the program DOCK was used to search for noncovalent inhibitors in 229,810 compounds of the ACD database. Of 56 tested compounds three had values <650pM, for example, compound 41 Ki = 26pM Fig. 16.6) [117]. The experimental X-ray structure of its complex with AmpC P-lactamase closely resembles the predicted binding mode. 

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