Computer-Aided Analysis and Design of Phosphonic and Phosphinic Enzyme Inhibitors as Potential Drugs and Agrochemicals

Abstract

A structure-based approach to design potent and selective inhibitors is an important component of the modern drug development process. As the altered activity of certain enzymes is associated with variety of pathologies, the design and synthesis of inhibitors for enzymes playing the key role in pathogenesis may result in potential therapeutic agents. Nowadays, the development of new inhibitors is often based on computer assisted design process. Although threedimensional structure of the enzyme and mechanism of enzymatic reaction are most important for accurate design, the mode of action of already known lead compounds as well as their characteristic structural features also have to be considered.This review summarises the current progress in computer-aided design of phosphonic and phosphinic acids and their short peptides as inhibitors of chosen enzymes of medical and agrochemical importance. Despite the mechanism of inhibitory activity two approaches for their design are presented. First one relies on the use of the crystal structure of enzymes as well as enzymes complexed with some ligands for structure-based search for novel inhibitory structures. Second enables prediction of activity of new enzyme groups of inhibitors based on the building-up relation of observed activity to specific structural features of sets of compounds of known biological activity.

New Drugs - From Necessity to Delivery

“…The activity of new compounds is then evaluated by imposing them on the pharmacophore. The process of searching for pharmacophores uses advanced mathematical methodscomputational intelligence or genetic algorithms, and is based on the findings regarding the biological inheritance of traits [24].…”

“…Generally, the experiment is a double-blind. Randomization reduces bias, while the existence of different comparison groups allows to determine any effects of the treatment in relation to the control group [24]. The process of the trial is long (about 5-7 years), requires the commitment of many clinics and of hundreds to thousands of patients from different places in the world.…”

Chemistry of Aminophosphonic Acids and Phosphonopeptides

“…Both herbicides are potent inhibitors of glutamine synthetase -an enzyme that catalyzes the conversion of L-glutamate into L-glutamine. The generally low toxicity and environmental compatibility of the compounds are stimulating factors in the continuing search for novel active molecules of this class as low-molecular-weight bioregulators [309].…”

Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives

“…Considering that lengths of O-P and C-P bonds are significantly longer than the corresponding O-C and C-C bonds, the phosphinic fragment might be considered as an extended tetrahedral intermediate and thus can be treated similar to the transition state of the hydrolysis (Figure 2) [21]. Moreover, they can act as simple analogues of amino acids replacing the carboxylic group by the phosphinic moiety, as non-hydrolysable phosphate analogues or as chelating agents of metal ions present in the active site of the enzymes [22]. A number of excellent reviews on various aspects of their activity in natural systems have been published [16,17].…”