title: Structural studies on bio-active compounds. 20. Molecular modeling and crystallographic studies on methylbenzoprim, a potent inhibitor of dihydrofolate reductase.
abstract: Methylbenzoprim (MBP) is a potent inhibitor of dihydrofolate reductase, which is more selective for mammalian than bacterial enzymes. Crystal-structure studies on the free base of MBP, with two independent molecules, and the ethanesulfonate salt, have demonstrated three significantly different conformations for MBP. With the MOPAC optimized MBP cation as starting point, the COSMIC energy was monitored as torsion angles were changed in 5 degrees increments. The barrier to rotation about C(5)-C(11) can create two slowly interconverting rotamers, in agreement with NMR studies. Two conformations of the cation that fit the human DHFR structure from the Brookhaven Protein Data Bank have been found. They differ chiefly by a half-turn about C(5)-C(11), positioning the nitro group on opposite sides but allowing the central and benzylic rings to find hydrophobic surroundings. The central ring is close enough to the predicted position of the cofactor NADPH to make competition likely. Kinetic studies with rat liver DHFR show that MBP is an inhibitor that competes with NADPH as well as dihydrofolate.
authors.affiliation: Department of Pharmaceutical Sciences, Aston University, Birmingham, United Kingdom.
authors.forename: B J
authors.initials: BJ
authors.lastname: Denny
authors.forename: N S
authors.initials: NS
authors.lastname: Ringan
authors.forename: C H
authors.initials: CH
authors.lastname: Schwalbe
authors.forename: P A
authors.initials: PA
authors.lastname: Lambert
authors.forename: M A
authors.initials: MA
authors.lastname: Meek
authors.forename: R J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: M F
authors.initials: MF
authors.lastname: Stevens
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D005492:Folic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D005493:Folic Acid Antagonists; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D005493:Folic Acid Antagonists; D011743:Pyrimidines; C064625:methylbenzoprim; C010920:dihydrofolate; D009249:NADP; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase