Tautomers are often disregarded in computer-aided molecular modeling applications. Little is known about the different tautomeric states of a molecule and they are rarely registered in chemical databases. Tautomeric forms of a molecule differ in shape, functional groups, surface, and hydrogen-bonding pattern. Calculation of physical-chemical properties and molecular descriptors differ from one tautomeric state to the other as it is demonstrated with an example of the log P calculation, similarity index, and the complementarity pattern to the targeted protein. Considering tautomery in ligand-protein interactions therefore has a significant impact on the prediction of the ligand binding using various docking techniques. This article points on hitherto unaddressed issue of tautomerism in computer-aided drug design.
The enzyme catechol O-methyltransferase (COMT) catalyzes the Me group transfer from the cofactor S-adenosylmethionine (SAM) to the hydroxy group of catechol substrates. Potential bisubstrate inhibitors of COMT were developed by structure-based design and synthesized. The compounds were tested for in vitro inhibitory activity against COMT obtained from rat liver, and the inhibition kinetics were examined with regard to the binding sites of cofactor and substrate. One of the designed molecules was found to be a bisubstrate inhibitor of COMT with an IC50 = 2 microM. It exhibits competitive kinetics for the SAM and noncompetitive kinetics for the catechol binding site. Useful structure-activity relationships were established which provide important guidelines for the design of future generations of bisubstrate inhibitors of COMT.
Herpes simplex virus type 1 thymidine kinase (HSV1-TK) has become increasingly important as a target in medicinal chemistry because of its links to therapy of viral infection, gene therapy of cancer and allogeneic transplantation. These applications are based on the differences in binding properties between the human and the viral enzyme. Several problems have been encountered in the clinic, e.g. the increase of resistance for antiviral drugs and the immunosuppressive effects of the dosages needed for tumor regression. Thus intensive efforts have been directed towards understanding substrate diversity to overcome the clinical limitations. In this context, kinetic and thermodynamic studies revealed that substrates bind in compulsory order and that the binding event is enthalpy driven. The structural evaluation of aciclovir resistant HSV strains shows that loss of electrostatic interactions, change in steric accessibility and modification of the 3D conformation of HSV1-TK are responsible for the encountered resistance. Further crystallography studies revealed the role of water in substrate binding, the advantage of a fixed ribose ring and that substrate acceptance of HSV1-TK is extended to all five nucleobases. The reviewed results give new rationale for the design of novel prodrugs and engineered HSV1-TK for antiviral and gene therapy.
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