MMPEP: Development and evaluation of peptide parameters for Allinger's MMP2(85) programme, including calculations on crambin and insulin

Wolfe, Saul; Weaver, Donald F.; Yang, Kiyull

doi:10.1139/v88-421

Cited by 27 publications

(7 citation statements)

References 53 publications

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“…Previously unknown MM2 parameters were found, where necessary, using established procedures (14,16). The parameters thus determined for the compounds to be discussed below are available as Supplementary ate rial.^ Each candidate was docked to 3 via the two hydrogen bonds already noted, and the relationship between the C=N of the candidate and the 0 -H of ser3 in the resulting complex was examined.…”

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confidence: 99%

Interactive design and synthesis of a novel antibacterial agent

Wolfe¹,

Jin²,

Yang³

et al. 1994

Can. J. Chem.

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. Can. J. Chem. 72, 105 1 (1994). P-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e.,fit) and catalytic (i.e. reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP from Streptomyces R61, the use of molecular mechanics calculations to treat "fit," and ab initio molecular orbital calculations to treat "reactivity," leads to the idea that the carboxyl group (GI) and the amide N-H (G2) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme-substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the p-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the p-lactam nitrogen. Molecular orbital calculations of structure-reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the p-lactam N-C(=O), comparable to a p-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (-AE > 10 kcaUmo1). Accordingly, structures containing a G1 and a G2 separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-l,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropy1)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, from D-and L-serine. The compound derived from L-serine is not active. The compound derived from D-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be canied out if modification of the lead structure leads to compounds with improved chemical stability. Toutefois, des essais prkliminaires ont suggCrC que le C=N de ce composC serait en Cquilibre avec les Cnamines endocycliques et exocycliques tautombres. Cette caractkristique nCcessite que la position C2 soit substituCe et que le groupe hydroxyle ne soit pas attach6 au carbone adjacent du C=N. On rencontre ces conditions dans une 2,2-dimCthy1-3-(2...

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confidence: 99%

Interactive design and synthesis of a novel antibacterial agent

Wolfe¹,

Jin²,

Yang³

et al. 1994

Can. J. Chem.

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“…A first requirement, the parameterization of MMP2(85) for peptides (MMPEP), has been published, along with a description of the expansion of the dimensions of the programme (1). A new, energy-based, subroutine, INIT, which searches 200,000 initial structures, has been written and incorporated into ECEPP.…”

Section: Discussionmentioning

confidence: 99%

Theoretical conformational analysis of peptides. Evolution of a strategy and its application to cholecystokinin analogs

Wolfe¹,

Bruder²,

Weaver³

et al. 1988

Can. J. Chem.

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. Can. J. Chem. 66,2703Chem. 66, (1988. Scheraga's ECEPP program has been used to determine the relationship between one-point energies and the energies minimized by a quadratic procedure, for different sized (+, +, x ,) dihedral angle grid searches of simple peptides. Based on these trials, a new subroutine, INIT, has been written and incorporated into the program. This subroutine calculates the one-point ECEPP energies of up to 200,000 random permutations of (4, +) = 0, + 90, 180 and (X ,) = -60, 180 with all w = X,] = 180; after each 40,000 permutations, the structures having the 10 lowest energies are ordered and selected for minimization. The ECEPP program has been modified further to provide an MMP2(85) input file as part of its normal output. This allows structures located by INIT to be minimized automatically, and then refined by the Newton-Raphson minimization and MMPEP parameters of MMP2(85).During the development of this protocol, it has been found that MMPEP correctly reproduces the C7 conformational preference of the alanyl dipeptide in nonpolar media, and also the experimentally observed shift to a~ and PII conformations in polar solvents, when the dielectric constant E = 78.5 D. This dielectric constant has, therefore, been selected for a conformational analysis, using INITIMMPEP, of the peptides Gly-Trp-Met-Asp-Phe-NH2 (GLMAP), Gly-D-Trp-Met-Asp-Phe-NH2 (GDMAP), and Gly-Gly-Met-Asp-Phe-NH2 (GGMAP); GLMAP is CCK-5, a cholecystokinin fragment possessing anticonvulsant activity, which is found in the brain. The analogs GDMAP and GGMAP are not active, or much less so than GLMAP. One strongly preferred structure has been found, in each case, for GLMAP (GLMAP3) and GDMAP (GDMAP39). These structures are very similar, in the nature of the edge-to-face stacking of their Trp and Phe aromatic rings, but the C-terminal regions differ. The conformation of the C-terminal tetrapeptide of GLMAP3 is identical to a previously calculated structure of CCK-4. A comparison of the C-terminal regions of GLMAP3 and GDMAP39 with the structure of 5,5-diphenylhydantoin suggests that the mechanisms of anticonvulsant action of phenytoin and CCK-5 are not the same. In the absence of an aromatic-aromatic interaction, no clear-cut conformational preference is found for GGMAP. The structure of GGMAP whose C-terminal region is the same as that of GLMAP3 (GGMAP20) is 1.51 kcal/mol higher in energy than the lowest energy structure, and lacks the hydrophobic wall provided by the Trp residue of GLMAP3. Au cours du dtveloppement de ce protocole, on a trouvt que MMPEP reproduit correctement la preference conformationnelle du C7 du dipeptide de l'alanyle dans des milieux non-polaues ainsi que le dtplacement observt exptrimentalement vers les conformations c i~ et PI1 dans des solvants polaires, lorsque E = 78,5 D. On a donc choisi cette constante ditlectrique pour une analyse conformationnelle, utilisant le programme INITIMMPEP, des peptides Gly-Trp-Met-Asp-Phe-NH2 (GLMAP), Gly-D-Trp-Met-Asp-Phe-NH2 (GDMAP) et Gly-Gly-Met-Asp-Phe-NH2 (...

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“…In agreement with ab initio calculation of Butterfloss and Hermans [42] and the force field parameterization procedure of Wolfe et al [43] we set the torsion barrier around the C-S bonds in the middle of the sulfur mustard molecule lower than the torsion barrier around the corresponding C-C bond in heptane. Less torsion restriction for sulfur mustard does not only lead to faster rotation around the central bonds than in heptane but also to a larger range of (non-equilibrium) conformations it can adopt.…”

Section: Characterization Of the Solute Moleculesmentioning

confidence: 93%