Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: docking between the antimalarial agent and its putative receptor.

Artemisinin (qinghaosu, QHS) is a promising new antimalarial agent that is effective against drug-resistant strains of malaria. The antimalarial activity of this drug appears to be mediated by an interaction of the drug's endoperoxide bridge with intraparasitic hemin. We have carried out a computer-assisted docking of QHS with hemin from various starting configurations and found that, in the most stable docked configuration, the endoperoxide bridge is in close proximity to the hemin iron. In contrast, an inactive analog, deoxyartemisinin (DQHS), docks in a different manner. Further computer analysis of the drug-hemin interaction might aid in the design of new QHS congeners.

Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand.

A series of compounds derived from phencyclidine (PCP) was examined in the sigma receptor and PCP receptor binding assays. The derivatives included compounds containing methylene, ethylene or carboxyl ethylene insertion between the cycloalkyl ring and the amine group of PCP. Various phenyl substitutions, cycloalkyl rings and amines of these derivatives were also examined. The methylene and ethylene insertions decreased the compounds' potencies at PCP receptors, whereas they increased the potencies at sigma receptors. The carboxyl ethylene insertion produced compounds with negligible potencies at PCP receptors while possessing high potencies for sigma receptors. One derivative (PRE-084; 2-(4-morpholino)ethyl 1-phenylcyclohexane-1-carboxylate hydrochloride) had an IC50 of 44 nM in the sigma receptor assay, an IC50 of more than 100,000 nM for PCP receptors and an IC50 higher than 10,000 nM in a variety of other receptor systems. In general, compounds with hydroxy-substituted phenyl groups tended to have decreased potency at sigma receptors, whereas methylphenyl and chlorophenyl substitutions increased potencies. Reduction of cycloalkyl ring size decreased potencies for sigma receptors and quaternized amine groups invariably lowered the compound's potencies. Conformational analysis indicated that PRE-084 fitted onto a pharmacophore model for the sigma ligands. The study describes a new, highly selective ligand for the sigma receptor. The results of this study also confirm distinctly different structural requirements for binding to sigma and PCP receptors and provide a new structural consideration for synthesizing sigma-selective compounds.

(+-)-Octahydro-2-methyl-trans-5 (1H)-isoquinolone methiodide: a probe that reveals a partial map of the nicotinic receptor's recognition site.

A new, semirigid, nicotinic agonist (+-)-octahydro-2-methyl-trans-5 (1H)-isoquinolone methiodide was synthesized. The disposition of this agonist's nitrogen and carbonyl group conforms well to the prevailing notion of a pharmacophore for the nicotinic receptor. Comparing its structure and electrostatic potential surfaces, we predicted that its activity would be similar to that of carbamylcholine at the frog neuromuscular junction. Instead, the potency of the isoquinolone was only 0.015 times as potent as (+)-carbamylcholine. We conclude, after eliminating other possibilities, that the vicinity of the carbonyl group of an agonist must be planar to fit a confined space within the receptor's recognition site. The isoquinolone is a weak agonist because its methylene group beta to the carbonyl intrudes on this space.

A graphical representation of the electrostatic potential and electric field on a molecular surface.

The graphics program presented, ARCHEM, draws the molecular electrostatic potential (MEP) on a molecular surface color-coded according to the magnitude of the potential. Vectors can be drawn on the surface to show the electric field surrounding the molecule and color-coded according to the magnitude of the field. The electrostatic potential (ESP) calculated from the wave function or from net atomic charges using GAUSSIAN 80 UCSF1.2 can be plotted at points on a shell surrounding the molecule. For the neurotransmitter glycine zwitterion, the MEP is calculated from the wave function and from different point charge models, and the results are represented graphically.

Carbamyl analogues of potent nicotinic agonists: pharmacology and computer-assisted molecular modeling study.

To investigate how the substitution of NH2 for CH3 affects the activity of three, potent, semirigid nicotinic agonists, carbamyl analogues were synthesized. The carbamyl agonists were 1-methyl-4-carbamyl-1,2,3,6-tetrahydropyridine methiodide (1), 1-methyl-4-carbamylpiperidine methiodide (2), and 1-methyl-4-carbamylpiperazine methiodide (3). Their potencies (reciprocals of the equipotent molar ratios) at the frog neuromuscular junction with reference to carbamylcholine were 0.77, 0.052, and 0.15, respectively. The acetyl analogues were more potent by factors of 65, 175, and 17, respectively. Explanations for this variable reduction in activity were sought by using computer-assisted molecular mechanics and calculations of electrostatic potential contours. Bioactive conformations of 1-3 were assigned on the basis of a well-supported pharmacophore and the ground-state conformation of the highly potent (50 times that of carbamylcholine) prototype, isoarecolone methiodide (4). Agonist 3 and its acetyl analogue superimposed closely in their ground-state, bioactive conformations, and the differences in their electrostatic potential contours were the least among the three pairs. Accordingly, their potencies differed the least. Agonists 1 and 2 both showed greater differences (with respect to their acetyl analogues) in their electrostatic potential contours and greater differences in potency. Agonist 2, in addition, could achieve the bioactive conformation only at the expense of 2.8 kcal mol-1, and, correspondingly, its activity relative to its acetyl analogue was lowest of all.

Synthesis, pharmacology, and molecular modeling studies of semirigid, nicotinic agonists.

Eight nicotinic agonists were synthesized, and their potencies were estimated by contracture of the frog rectus abdominis muscle. The most potent, 1-methyl-4-acetyl-1,2,3,6-tetrahydropyridine methiodide (3b), 50 times as potent as carbamylcholine, served as a template for the rest. Although all of the agonists could easily conform to the putative nicotinic pharmacophore, their potencies spanned a nearly 10,000-fold range. This pharmacophore, therefore, may be necessary but deficient. Computer-assisted molecular modeling studies helped to delineate additional factors that may contribute to potency. The factors are (1) the ground-state conformation, (2) superimposability of the hydrogen bond acceptor and the cationic head onto the template, (3) electrostatic potential at the cationic head and at the hydrogen bond acceptor site, and (4) the presence of a methyl group bonded to the carbon atom that bears the hydrogen bond acceptor. A new program, ARCHEM, was used to calculate and to visualize electrostatic potentials at the van der Waals surfaces of the agonists.

Supercomputer applications in molecular modeling.

An overview of the functions performed by molecular modeling is given. Molecular modeling techniques benefiting from supercomputing are described, namely, conformation, search, deriving bioactive conformations, pharmacophoric pattern searching, receptor mapping, and electrostatic properties. The use of supercomputers for problems that are computationally intensive, such as protein structure prediction, protein dynamics and reactivity, protein conformations, and energetics of binding is also examined. The current status of supercomputing and supercomputer resources are discussed.

Structural and electronic requirements for potent agonists at a nicotinic receptor.

A new agonist, isoarecolone methiodide (1,1-dimethyl-4-acetyl-1,2,3,6-tetrahydropyridinium iodide) was tested at the frog neuromuscular junction. It was 50 times more potent than carbamylcholine, making it one of the most potent nicotinic agonists known. In addition, its cyclic structure and conjugated carbonyl bond endow it with near rigidity. An analogous compound, 1,1-dimethyl-4-acetylpiperazinium iodide, was synthesized because of its similar geometry and rigidity. It was 2.6 times as potent as carbamylcholine but only 0.053 times as potent as isoarecolone methiodide. Computer assisted molecular modeling and molecular orbital calculations revealed steric and electrostatic field differences between these two compounds.