It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.

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Fluorine in medicinal chemistry.

The Many Roles for Fluorine in Medicinal Chemistry

▪ Abstract Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the over...

/pdf/pleiotropic-effects-of-statins-1b9b1g8457.pdf

Pleiotropic effects of statins

The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ hete...

http://www.digestivo.fmed.edu.uy/Materiales/AMP%20kinasa.pdf

AMPK in Health and Disease

http://www4.utsouthwestern.edu/moleculargenetics/pdf/msb_cur_res/2006%20CELL%20Goldstein%2035.pdf

Protein Sensors for Membrane Sterols

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.

https://science.sciencemag.org/content/sci/292/5519/1160.full.pdf

Structural mechanism for statin inhibition of HMG-CoA reductase.

3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the formation of mevalonate, the committed step in the biosynthesis of sterols and isoprenoids. The activity of HMGR is controlled through synthesis, degradation and phosphorylation to maintain the concentration of mevalonate-derived products. In addition to the physiological regulation of HMGR, the human enzyme has been targeted successfully by drugs in the clinical treatment of high serum cholesterol levels. Three crystal structures of the catalytic portion of human HMGR in complexes with HMG-CoA, with HMG and CoA, and with HMG, CoA and NADP+, provide a detailed view of the enzyme active site. Catalytic portions of human HMGR form tight tetramers. The crystal structure explains the influence of the enzyme's oligomeric state on the activity and suggests a mechanism for cholesterol sensing. The active site architecture of human HMGR is different from that of bacterial HMGR; this may explain why binding of HMGR inhibitors to bacterial HMGRs has not been reported.

/pdf/crystal-structure-of-the-catalytic-portion-of-human-hmg-coa-4g4bjla0ua.pdf

Crystal structure of the catalytic portion of human HMG‐CoA reductase: insights into regulation of activity and catalysis

The structure of the catalytic portion of human HMG-CoA reductase

The crystal structure of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies.

Diffraction-quality crystals of the bifunctional enzyme fructose 6-phosphate, 2-kinase:fructose 2,6-bisphosphatase from rat testis have been obtained. The crystals were grown in the presence of ATP gamma S, fructose 6-phosphate, the detergent n-octylglucoside, and the precipitant polyethylene glycol 4000. The crystals have the symmetry of the trigonal space group P31/221 with a = b = 83.0 A and c = 130.6 A. Flash-frozen crystals diffract to beyond 2.2 A, and native data have been collected.

/pdf/crystallization-and-preliminary-x-ray-analysis-of-fructose-6-wshij9vdst.pdf

Eva S. Istvan

Papers

Structural mechanism for statin inhibition of HMG-CoA reductase.

Crystal structure of the catalytic portion of human HMG‐CoA reductase: insights into regulation of activity and catalysis

The structure of the catalytic portion of human HMG-CoA reductase

The crystal structure of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies.

Crystallization and preliminary X-ray analysis of fructose 6-phosphate, 2-kinase:fructose 2,6-bisphosphatase.