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Våbenø, Jon, Nikiforovich, G. V. and Marshall, G. R. A Minimalistic 3D Pharmacophore Model for Cyclopentapeptide CXCR4 Antagonists. Biopolymers, Wiley Periodicals, Inc. (2006) [PDF]

Ye, Yunpeng, Liu, M., Kao, J. L.-F. and Marshall, G. R. Novel Trihydroxamate-Containing Peptides: Design, Synthesis, and Metal Coordination. Biopolymers, J. Peptide Sci. (2006) [PDF]

Anderson, Matthew A., Ogbay, B., Arimoto, R., Sha, W., Kisselev, O. G., Cistola, D. P. and Marshall, G. R. Relative Strength of Cation-π vs Salt-Bridge Interactions: The G_tα (340—350) Peptide/Rhodoopsin System. J. Am. Chem. Soc., 128:7531-7541 (2006) [PDF]

Nikiforovich, Gregory V. and Marshall, G. R. 3D modeling of the activated states of constitutively active mutants of rhodopsin. Biochem. & Biophy. Res. Comm. (BBRC), 345:430-437 (2006) [PDF]

Che, Ye and Marshall, G. R. Engineering Cyclic Tetrapeptides Containing Chimeric Amino Acids as Preferred Reverse-Turn Scaffolds. J. Med. Chem., 49:111-124 (2006) [PDF]

Kuster, Daniel J., and Marshall, G. R. Validated ligand mapping of ACE active site. J. Comp.-Aided Molec. Design, (Sept 3, 2005) [Full Article-PDF]

Anderson, Lori L., Marshall, G. R., Crocker, E., Smith, S. O., and Baranski, T. J. Motion of Carboxyl Terminus of Ga is Restricted upon G-Protein. J Biol Chem, 280(35):31019-31026, (Sept 2, 2005) [Full Article-PDF]

Che, Ye and Marshall, G. R. Impact of Azaproline on Peptide Conformation. J Org Chem, 69(26):9030-9042 (2005) (published on the web, Nov 2004) [Full Article-PDF]

Marshall, Garland R. and Riley, Dennis P. Design of Protein and Enzyme Mimetics. [Manuscript-PDF (in Press)]

Che, Ye and Marshall, Garland R. Impact of Cis-Proline Analogs on Peptide Conformation. [Manuscript-PDF (in Press)]

Anderson, Matthew, A., Arimoto, Rieko, Sha, Wei, Kisselev, Oleg G. and Marshall, Garland R. Cation-Pi Interactions: Are They Worth Their Salt? [Manuscript-PDF (in press)]

Berglund, Anders, Head, R. D., Welsh, E. A. and Marshall, G. R. ProVal: A Protein-Scoring Function for the Selection of Native and Near-Native Folds. PROTEINS: Structure, Function, and Bioinformatics 54:289-302 (2004). [Full Article-PDF]
[ProVal Program]

Poreddy, Amruta R., Schall, O. F., Osiek, T. A., Wheatley, J. R., Beusen, D. D., Marshall, G. R. and Slomczynska, U. Hydroxamate-Based Iron Chelators: Combinatorial Syntheses of Desferrioxamine B Analogues and Evaluation of Binding Affinities. J Comb Chem, 6:239-254 (2004). [Full Article-PDF]

Anderson, Lori L., Marshall, G. R. and Baranski, T. J. Expressed Protein Ligation To Study Protein Interactions: Semi-Synthesis of the G-Protein Alpha Subunit. Protein Peptide Lett. (in press) 2004.

Ye, Y., Min Liu, Jeff L.-K. Kao and G. R. Marshall. Peptide-Bond Modification for Metal Coordination: Peptides Containing Two Hydroxamate Groups. Peptide Science (Biopolymers) 71(4):489-515 (2003). [Full Article-PDF]

Ye, Yunpeng, W. P. Li, C. J. Anderson, J. Kao, G. V. Nikiforovich and S. Achilefu. Synthesis and Characterization of a Macrocyclic Near-Infrared Optical Scaffold, J Am Chem Soc (Communications), 125:7766-7767, (2003). [Full Article-PDF]

Zhang, Wei-Jun, A. Berglund, J. L.-F. Kao, J.-P. Couty, M. C. Gershengorn and G. R. Marshall, Impact of Azaproline on Amide Cis-Trans Isomerism: Conformational Analyses and NMR Studies of Model Peptides Including TRH Analogues, J. Am. Chem. Soc. 125:1221-1235, (2003). [Full Article-PDF]

Marshall, Garland R., Solid Phase Synthesis: A Paradigm Shift (This is a preprint of an article accepted for publication in Journal of Peptide Science, Copyright © 2003 John Wiley & Sons Ltd and the European Peptide Society.) [Full Article-PDF]

Nikiforovich, Gregory V. and Garland R. Marshall, Three-Dimensional Model for Meta-II Rhodopsin, an Activated G-Protein-Coupled Receptor, (This is a preprint of an article accepted for publication in the Journal of Biochemistry, American Chemical Society.) (2003) [Full Article-PDF]

Di Santo, Roberto, R. Costi, M. Artico, S. Massa, R. Ragno, G. R. Marshall and P. La Colla, Design synthesis and QSAR studies on N-aryl heteroarylisopropanolamines, a new class of non-peptidic HIV-1 protease inhibitors, Bioorg. Med. Chem. 10:2511-2526 (2002). [Full Article-PDF]

Marshall, Garland R., R. Head and R. Ragno, Affinity Prediction: The Sine Qua Non, Chapter 3, Thermodynamics in Biology, pp. 87-111, (2002).

Reaka, Andrea J. H., Ho, Chris M. W. and Marshall, Garland R., Metal complexes of chiral pentaazacrowns as conformational templates for Beta-turn Recognition, J. Comp. Aided Molec. Des., 16:585-600, (2002). [Full Article-PDF]

Arimoto, Rieko, O. G. Kisselev, G. M. Makara and G. R. Marshall, Rhodopsin-Transducin Interface: Studies with Conformationally Constrained Peptides, Biophy. J. 81:3285-3293, Dec. (2001). [Full Article-PDF]

Bourne, Gregory T., S. W. Golding, R. P. McGeary, Wim D. F. Meutermans, A. Jones, G. R. Marshall, P. F. Alewood, and M. L. Smythe, The Development and Application of a Novel Safety-Catch Linker for BOC-Based Assembly of Libraries of Cyclic Peptides, J. Org. Chem., 66:7706-7713 (2001). [Full Article-PDF]

Galaktionov, S., G. V. Nikiforovich and G. R. Marshall, Ab Initio Modeling of Small, Medium, and Large Loops in Proteins, Biopolymers (Peptide Science), 60:153-168 (2001). [Full Article-PDF]

Galaktionov, S., G. V. Nikiforovich and G. R. Marshall, 3D Models for Conformational States of the V3 and V1/V2 Loops in gp120/CD4/Antibody Complex, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 394-395 (2001). [Abstract-PDF]

Heshmati, Parissa, J. Whitehurst and G. R. Marshall, Solid-Phase Synthesis Utilizing Azido-alpha-Amino Acids: Reduction of Azido-Protected Proline, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 240-241 (2001). [Abstract-PDF]

Marshall, G.R., A. Nauk, P.A. Reddy, O.F. Schall, D.D. Beusen, Y. Ye, and U. Slomczynska. Chapter 5: Combinatorial Chemistry of Metal-Binding Ligands. In: Advances in Supramolecular Chemistry, vol. 8, G.W. Gokel, Ed., SunCoast Press, Inc., pp. 175-243 (2001). [Full Chapter-PDF]

Marshall, Garland R., From Merrifield to MetaPhore: A Random Walk with Serendipity (The Merrifield Award Lecture), Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 3-11 (2001). [Abstract-PDF]

Marshall, Garland R., Peptide Interactions with G-Protein Coupled Receptors (*This paper is to honor the 80th birthday of Professor R. Bruce Merrifield, my mentor, friend and role model.), Biopolymers (Peptide Science), 60(3):246-277, 2001. [Full Article-PDF]

Ming, SUN, Y. Che, M. Fangming and G. R. Marshall, Conformational analysis on anti-HIV-1 peptide T22 ([Tyr5,12,Lys7]-polyphemusin II), Chinese Science Bulletin 46(20):1685-1688 (2001).

Nikiforovich, G. V. and G. R. Marshall, Issue Co-Editors, Editorial: Current Developments in Computational Studies of Peptides, Biopolymers (Peptide Science), 60:77-78 (2001). [Full Editorial-PDF]

Nikiforovich, G. V., S. Galaktionov, J. Balodis and G. R. Marshall, Novel approach to computer modeling of seven-helical trans-membrane proteins: Current progress in the test case of bacteriorhodopsin, Acta Biochimica Polonica, 48(1):53-64 (2001). [Full Article-PDF]

Nikiforovich, G. V. and G. R. Marshall, 3D Model for TM Region of the AT-1 Receptor in Complex with Angiotensin II Independently Validated by Site-Directed Mutagenesis Data, Biochemical and Biophysical Research Communications, 286:1204-1211 (2001). [Full Article-PDF]

Nikiforovich, G. V., G. Lindeberg, K E. Kover, Y. Ye, P.-A. Frandberg, F. Nyberg, A. Karlen, A. Hallberg and G. R. Marshall, Cyclopentapeptides as Rigidified Templates for Probing Interactions with the AT-1 Receptors, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 917-918 (2001). [Full Article-PDF]

Reddy, P. A., O. F. Schall, J. R. Wheatley, L. O. Rosik, J. P. McClurg, G. R. Marshall, and U. Slomczynska, O-Protected N-(2-Nitrophenylsulfonyl)hydroxylamines: Novel Reagents for the Synthesis of Hydroxamates, Synthesis (Journal of Synthetic Organic Chemistry) 7:1086-1092 (2001).

Sha, Wei, R. Arimoto and G. R. Marshall, Receptor-Bound Conformation of a alpha-Peptide of Transducin (Gt) is not Stabilized by a "pi-Cation" Interaction but by Constrained Lactam Bridges Between Residues 341 and 350, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 909-910 (2001). [Abstract-PDF]

Slomczynska, U., P. A. Reddy, P. F. Schall, T. Osiek, A. Naik, W. B. Edwards, J. Wheatley and G. R. Marshall, Combinatorial Syntheses of Polyhydroxamate Siderophores: Desferrioxamine, Exochelin, Mycobactin, and Aerobactin Libraries, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society 2nd International Peptide Symposium/17th American Peptide Symposium, 177-179 (2001). [Abstract-PDF]

Zhang, Wei-Jun, P. Heshmati, Y. Ye and G. R Marshall, Solid-Phase Synthesis and Chemical Ligation of Transmembrane Segments of Rhodopsin, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society 2nd International Peptide Symposium/17th American Peptide Symposium, 836-837 (2001). [Abstract-PDF]

Ye, Yunpeng and G. R. Marshall, Convenient Conversion of Amino Acids to Their N-Hydroxylated Derivatives on a Solid Support: Synthesis of Hydroxamate-Based Pseudo-Peptides, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 589-590 (2001). [Abstract-PDF]

Ye, Yunpeng and G. R. Marshall, Peptide Bond Modification for Metal Coordination: 1. Metal-Binding Properties of Hydroxamate-Based Pseudo-Peptides, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 591-592 (2001). [Abstract-PDF]

Ye, Yunpeng, G. R. Marshall, R. Smith, C. Durmstorff and U. Slomczynska, Peptide Bond Modification for Metal Coordination: 2. Metal-Binding Properties of Peptide-Derived Pentaaza-Macrocyclic Templates, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 593-594 (2001). [Abstract-PDF]

Ye, Yunpeng and G. R. Marshall, Peptide Bond Modification for Metal Coordination: 3. Metal-Binding Properties of Phosphorus-Based Pseudo-peptides, Peptides: The Wave of the Future, Michael Lebl and Richard A. Houghten (Eds.), American Peptide Society, 2nd International Peptide Symposium/17th American Peptide Symposium, 595-596 (2001). [Abstract-PDF]

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Beusen, D.D. and G.R. Marshall, Pharmacophore Definition Using the Active Analog Approach, in: Pharmacophore Perception, Development, and Use in Drug Design, Osman F. Guner, Ed. International University Line, La Jolla, CA. (2000), pp. 21-45.

Introduction: Although modern methods in molecular biology and biophysics have enhanced the likelihood that a drug discovery effort will be based on a detailed atomic structure of the target, the fact is that pharmacology generally precedes receptor structural data. In most cases, the medicinal chemist is forced to offer novel compounds to the target and hope for consistent responses which enable inference of its three-dimensional structure. Ideally, the resulting operational model provides predictive value when considering new compounds for synthesis and biological testing.The intellectual framework for utilizing structure-activity data to extrapolate information regarding the receptor is the pharmacophore. A concept introduced by Ehrlich at the turn of the century, this is the critical three-dimensional arrangement of molecular fragments (or distribution of electron density) that is recognized by the receptor and, in the case of agonists, causes subsequent activation of the receptor upon binding. In other words, some parts of the molecule are essential for interaction, and they must be capable of asuming a particular three-dimensional pattern that is complementary to the receptor in order to interact favorably. The pharmacophore construct leads to a problem statement composed of two processes. First is the determination, by chemical modification and biological testing, of the relative importance of different funtional groups in the drug to receptor recognition. This can give some indication of the nature of the functional groups in the receptor responsible for binding of the set of drugs. Second, a hypothesis is proposed concerning correspondence between functional groups in different congeneric series of the drug.

Marshall, G.R., R.H. Head and R. Ragno. Affinity Prediction: The Sina Qua Non. In Thermodynamics in Biology, E. Di Cera, ed. Oxford University Press (2000) pp. 87-111.

Introduction: Significant advances in molecular biology, x-ray crystallography, and NMR spectroscopy provide three-dimensional structures of potential therapeutic targets at atomic resolution at an increasing rate. Coupled with concomitant increases in accessible computing power, and in understanding of the physical chemical basis of molecular interactions, these advances have fostered a new era of rational drug design. Compounds in clinical use as HIV antivirals are a testimony to the effectiveness of iterative structurally based design. Many structurally based drug-design software packages now exist (Bohm, 1992; Ho and Marshall, 1994; Pearlman and Murko, 1993; Rotstein and Murcko, 1993) which assist in the design of novel ligands as potential therapeutics. No matter what algorithmic method of ligand design is utilized, an essential part of the process is the prediction of the affinity for the receptor of the designed ligands, both in their construction and to assist in synthetic prioritization. Affinity for the macromolecular target is, after all, an essential requirement, a sine qua non.

Nikiforovich, G.V., K.E. Kover, W.-J. Zhang and G.R. Marshall, Cyclopentapeptides as Flexible Conformational Templates for Receptor Probes. J. Am. Chem. Soc. 122(14):3262-3273 (2000). [Full Article-PDF] [Abstract-PDF]

Ragno, R., G.R. Marshall, R. Di Santo, R. Costi, S. Massa, R. Pompei and M. Artico, Antimycobacterial Pyrroles: Investigation by a CoMFA-QSAR Hybrid Model of Differently Substituted Pyrroles Active against Mycobacterium tuberculosis. Bioorg. Med. Chem. 8:1423-1432 (2000). [Full Article-PDF]

Tong, Yunsong, Olczak, J., Zabrocki, J., Gershengorn, M.C., Marshall, G.R. and Moeller, K.D. Constrained Peptidomimetics for TRH: cis-Peptide Bond Analogs. Tetrahedron 56:9791-9800 (2000). [Full Article-PDF]

Zhang, Wei-Jun, Berglund, A., Gershengorn, M. C., Kao, J. and Marshall, G. R. [AzPro3]-TRH: Impact of Azaproline on Cis-Trans Isomerism. Peptides 2000, Proc. 26th Euro. Pept. Symp., J. Martinez, Ed.(2000).

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Duclohier, H., K. Kociolek, M. Stasiak, M.T. Leplawy and G.R. Marshall. C-terminally shortened alamethicin on templates: Influence of the linkers on conductance. Biochim. Biophys. Acta 1420:14-22 (1999). [Full Article-PDF]

Marshall, G.R., Ragno, R., Makara, G.M., Arimoto, R. and Kisselev, O. Bound Conformation for Ligands for G-Protein Coupled Receptors. Lett. Peptide Sci., 6:283-288 (1999).

Summary: The conformation of the C-terminus of the alpha-subunit of transducin, the G-protein of vision, has been determined by transfer NOE when bound to activated (MII) rhodopsin. One hundred three new NOE constraints are apparent when light is shown on a mixture of rhodopsin bilayers and the undecapeptide. Analogs of the alpha-peptide with covalent constraints were designed restricting the bound conformation; they stabilize MII thus supporting the deduced structure. The NMR structure of a complex of the intracellular loops of rhodopsin facilitates docking of the alpha-peptide and also shows proximity of residues known by mutational analysis to interact to generate the activated rhodopsin-transducin interface. This constrains the location of transmembrane helices in the structure of activated rhodopsin. Methods for the prediction of affinity have been used to estimate the relative binding constants of peptide analogs with the loop complex and show strong correlation with experimental data. Various models of the rhodopsin-transmembrane helical segments have been computationally fused with distance geometry to determine the overall model which best fits the experimental data on the rhodopsin-transducin interface.

Kisselev, O., Y.C. Fann, J. Kao, J. Ponder, N. Gautam, and G. R. Marshall. Light-Activated Rhodopsin Induces Structural Binding Motif in G-Protein Alpha Subunit. Proc. Natl. Acad. Sci. USA 95:4270-4275(1998).[Full Article-PDF]

Nikiforovich, G. V., Galaktionov, S., Tseitin, V. M., Lowis, D. R., Shenderovich, M.D. and Marshall, G. R. 3D modeling for TM receptors: Algorithms and validations. Lett. Pep. Sci. 5:413-415 (1998).

Summary: This paper outlines the basic strategy to build 3D models of transmembrane G-protein coupled receptors (GPCRs) starting from their amino acid sequences in a 'block-by-block' manner: (i) locate possible TM helical fragments in the GPCR sequence; (ii) build 3D structures for these helices; (iii) arrange isolated helices across the membrane; (iv) calculate all pairwise helix-helix interactions; (v) assemble helical bundle(s); (vi) restore interhelical loops and N- and C- termini; and (vii) refine the entire 3D structure(s). Computer algorithms and preliminary results for most of the steps are discussed.

Oprea, T.I. and G.R. Marshall. Receptor-Based Prediction of Binding Affinities. Perspectives Drug Discovery Des. 9/10/11:35-61 (1998). (No abstract)

Takeuchi, Y., and G.R. Marshall. Conformational Analysis of Reverse-Turn Constraints by N-Methylation and N-Hydroxylation of Amide Bonds in Peptides and Non-Peptide Mimetics. J. Am. Chem. Soc. 120(22); 5363-5372 (1998). [Full Article-PDF]

Takeuchi, Y., E.F.B. Shands, D.D. Beusen, and G.R. Marshall. Derivation of a Three-Dimensional Pharmacophore Model of Substance P Antagonists Bound to the Neurokinin-1 Receptor. J. Med. Chem. 41(19):3609-3623 (1998). [Full Article-PDF]

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Marshall, G. R. Therapeutic Approaches to Human Immunodeficiency Virus: Structural Studies on G-Protein-Coupled Receptors. Pharmacol. Ther. 76:135-139 (1997). [Full Article-PDF]

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Abstract: Nature selects the genetic code table to have a nimimum risk caused by a point mutation (a misprint in a text of nucleotide sequence). The purpose of this paper is to accurately formulate and verify this hypothesis. The "nothing" is (1) the code table is a map: codon-- amino acid; (2) the structure of amino acids in 3D-space is known.

Abstract: The incorporation of cis- and trans-3-mercaptoproline (3-MCc and 3-MPt) into analogs of biologically active peptides has been shown to be an effective means for reducing the conformational mobility of the peptide backbone. We report herein a novel stereoselective synthetic route to L-1 and L-2, derivatives of 3-MPt and 3-MPc suitably protected for solid phase peptide synthesis. The optically active starting material was the previously reported cis-3-hydroxyprolinol derivative L-3. Oxidation of the C1 alcohol to the carboxylic acid, formation of the methyl ester and deprotection of the C3 alcohol yielded L-6 in an overall yield of 68%. Reaction of the secondary alcohol with thiolacetic acid under Mitsunobu conditions gave the thiolacetate L-7 in 77% yield with clean inversion of configuration. Conversion of L-7 to L-1 was accomplished in a one-pot sequence consisting of three steps: hydrolysis of the thiolacetate, formation of the thioether and hydrolysis of the methyl ester. The overall yield of L-1 from L-3 was 38%. Synthesis of L-2 required an epimerization of L-6, which was accomplished using a standard Mitsunobu inversion to give the trans-3-hydroxyproline derivative L-8. Transformation of L-8 to L-2 followed that described for L-1, except that removal of the methyl ester from L-10 required acidolysis in refluxing 4 N HC1. The overall yield of L-2 from L-3 was 18%. The availability of pure enantiomers of 3-MPt and 3-MPc protected for SPPS will greatly facilitate their use as conformational constraints for studying peptide-receptor interactions.

Zhang, W-J, G.V. Nikiforovich, J. Pérodin, D.E. Richard, E. Escher, G.R. Marshall. Novel Cyclic Analogs of Angiotensin II with Cyclization between Positions 5 and 7: Conformational and Biological Implications. J. Med. Chem. 39(14):2738-2744 (1996). [Full Article-PDF]

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Abstract: Potent, cyclic hexapeptide analogues of somatostatin are generally believed to adopt some common secondary structural features: alpha II'beta turn at one end of the cycle, and a type VI turn with a cis amide bond at the other. A proposed cis amide surrogate, the 1,5-disubstituted tetrazole, has been placed into a cyclic hexapeptide analog of somatostatin in order to constrain the putative cis amide bond. The final cyclization was done by either chemical or enzymatic means. The product, cycle (Ala(6)-Tyr(7)-D-Trp(8)-Lys(9)-Val(10)-Phe(11)-Psi[CN4]), was found to have 83% of the activity of somatostatin. Solution nmr analysis in DMSO/water revealed that the backbone as well as side chain chi(1) and chi(2) were well ordered. Relaxation matrix methods were rued to extract distance restraints from the nuclear Overhauser effect spectroscopy data set, and these were used in a systematic search of torsional space to identify structures consistent with the nmr data. Restrained minimizations of these structures using a number of different force fields produced structures having the expected beta II' turn at D-Trp(8)-Lys(9) and a beta VIa turn in the Phe(11)-Psi[CN4]-Ala(6) portion of the molecule. The similarity of the minimized structures to those previously reported for cyclic hexapeptide analogies of somatostatin confirms the similarity of the tetrazole geometry To that of the cis amide in solution.

Cornille, F., U. Slomczynska, M.L. Smythe, D.D. Beusen, K.D. Moeller and G.R. Marshall. Electrochemical cyclization of dipeptides toward novel bicyclic, reverse-turn peptidomimetics: Synthesis and conformational analysis of 7,5-bicyclic systems. J. Am. Chem. Soc. 117:909-917 (1995). [Full Article-PDF]

Abstract: Three new strategies for sampling the conformation space accessible to a series of structurally diverse, flexible molecules are defined and compared to samples obtained using a fixed-grid torsion angle sampling strategy. A set of 28 potent inhibitors of angiotensin converting enzyme selected by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3] and the unrestricted active-site model proposed by Waller et al. [to be published] are used to produce a realistic experimental setting. We modified our Constrained Search algorithm [Dammkoehler et al., J. Comput.-Aided Mol. Design, 3 (1989) 3] to support these new sampling strategies, performing a series of 64 simulations (search experiments) and generating a large set of sterically allowed conformations. In each experiment, we systematically vary the internal torsion angles in each molecule using one of the sampling strategies. The common orientations of preselected functional groups thought to represent those dominating the interaction with the enzyme and presented by the set of molecules are classified and recorded for each experiment. Pairwise distances between groups are used to characterize the geometry of the common orientations. The results of each experiment, represented by a set of distance values, are compared and combined to evaluate the completeness of the conformational sampling. While no pure strategy or single search experiment was found to be adequate to fully explore the set of common sterically allowed conformations, a new sampling technique, called adaptive radial sampling, is shown to be significantly more complete than the commonly used fixed grid sampling.

Summary: DBMAKER is a program that, in conjunction with CONCORD, generates three-dimensional structural databases. Numerous user-defined parameters monitor content, composition, size and connectivity information, but allow the program to generate random compounds within the scope of these constraints. SMILES string representations are generated, and conversion to 3D is performed by CONCORD. This assures high-quality 3D structures and portability to numerous proprietary storage formats. Methods are described to maintain compound registration, allowing database expansion as required without duplication.

Abstract: Data have been measured at two temperatures, 293 K and 107 K, for a crystal of a thyrotropin-releasing hormore analogue, pGlu-Phe-D-Pro-Y [CN4]-NMe, C20H25N7O3, and the structures solved and refined. The tripeptide contains a tetrazole ring which mimics a cis-peptide bond at the C terminus. An intermolecular hydrogen bond exists between two molecules related by the twofold screw axis, resulting in infinite chains of hydrogen-bonded peptide molecules. Because of the folding and packing of the molecules, there are no intermolecular contacts of less than 4 Å to the N atom of the phenylalanine residue.

Abstract: The respiratory epithelial pathology of pertussis (whooping cough) can be reproduced by tracheal cytotoxin (TCT), a disaccharide-tetrapeptide released by Bordetella pertussis. TCT is a muramyl peptide, a class of peptidoglycan-derived compounds which have many biological activities including adjuvanticity, somnogenicity, pyrogenicity, and cytotoxicity. The structural requirements for muramyl peptides to produce some of these biological effects have been partially characterized. Using in vitro assays with respiratory epithelial cells and tissue, we have previously determined that the disaccharide moiety of TCT is not involved in toxicity and that the side-chain functional groups of diaminopimelic acid (A(2)pm) are crucial for toxicity. In this study, we determine the importance of every amino acid, functional group and chiral centre in the peptide portion of TCT. Although lactyl tetrapeptides are the most toxic of the TCT fragments, producing dose-response curves identical to TCT, the smallest analogues of TCT which are active in our assay are of the form X-gamma-(D)-Glu-meso-A(2)pm, where X may be an amino acid or a blocking group. Within this active substructure, main-chain chirality and all functional groups are essential for toxicity. This definition of the core region of TCT indicates that the TCT interaction site is unlike almost all other muramyl peptide interaction sites for which structure-activity data are available.

Introduction: By historical imperative, the role of molecular modeling in drug design has been divided into two separate paradigms: one centered on the structure-activity problem, which attempts to rationalize biological activity in the absence of detailed, three-dimensional structural information about the receptor, and the other focused on understanding the interactions seen in receptor-ligand complexes, which uses the known three-dimensional structure of the therapeutic target to design novel drugs. The rapid increase in relevant structural information, as a result of advances in molecular biology that is used to generate the target proteins in adequate quantities for study, and the equally impressive gains in NMR (1-3) and crystallography that provide three-dimensional structures have stimulated the need for design tools, and the molecular modeling community is rapidly evolving useful approaches. The more common problem, however, is one in which the receptor can only be inferred from pharmacological studies and little, if any, structural information is available to guide modeling. Nevertheless, useful information that can guide the design and synthesis of potential novel therapeutics can be developed from an analysis of structure-activity data in the three-dimensional framework provided by current molecular modeling techniques. While most of the techniques and approaches described here have broader application than shown, the examples chosen should be sufficient to illustrate their use. A number of reviews (4-8) of computer-aided drug design have relevant sections covering portions of this chapter and are recommended for a more complete overview.

Abstract: The sequence of a cholecystokinin (CCK) related peptide was modified to obtain analogues, which interact selectively either with CCK-B, or with d-opioid receptors. Two kinds of peptides were designed, namely, the cyclic peptides of the H-Tyr-cyclo (D-Pen-Gly-Trp-L/D-3-trans-mercaptoproline)-Asp-Phe-NH2 sequence (compounds 1a and 1b, respectively), and the linear peptides of the H-Tyr-D-Val-Gly-Trp-L/D-3-trans-methylmercaptoproline-Asp-Phe-NH2 sequence (compounds 2a and 2b, respectively). The only difference between the chemical structures of the linear analogues compared to the cyclic ones is that one covalent bond has been eliminated and a sulfur atom is replaced by a methyl group. Molecular modeling showed that, among low-energy conformers of cyclic compounds 1, there are three-dimensional structures compatible to the model for d-receptor-bound conformer, suggested earlier [G. V. Nikiforovich, V. J. Hruby, O. Prakash and C. A. Gehrig (1991) Biopolymers, Vol. 31, pp. 941-955]. Results of binding assays fully supported the rationale for the design of compounds 1 and 2. The cyclic analogue 1a has Ki values of 4.5 and >5000 nM at d-and µ-opioid receptors, respectively;1C50 values of 3000 nM for both CCK-A and CCK-B receptors, whereas its linear counterpart 2a has Ki values of 462 and 229 nM at d- and µ-opioid receptors, respectively; and 1C50 values of 1.6 and > 10,000 nM for CCK-A and CCK-B receptors, respectively. The results of this study demonstrate a possibility to redirect a peptide sequence that interacts with one type of receptors (CCK-B receptors) toward interaction with another type (d-opioid receptors) belonging to a different physiological system. This redirection could be performed by changing the conformational properties of the peptide with very minimal changes in its chemical structure.

Smythe, M.A., S.E. Huston and G. R. Marshall. The molten helix: effects of solvation on the a- to 310-transition. J. Am. Chem. Soc. 117:5445-5452 (1995). [Full Article-PDF]

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