aaaaaaaaa Research » Gregory V. Nikiforovich - Cogito ergo sum
Gregory V. Nikiforovich                   COGITO  ERGO  SUM
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MolLife Design LLC
LOG: Aug. 13, 2017

3D Modeling of G-Protein Coupled Receptors

Drug Design Based on Computational Studies of Peptides

  3D Modeling of G-Protein Coupled Receptors.
G-protein coupled receptors (GPCRs) are essential players in myriad biological processes, including olfaction, photoreception, taste, hormone signaling, neurotransmitter activation, etc., and are the targets of numerous pharmaceutical agents. It has been estimated that over 50% of therapeutic compounds in use act on GPCRs. During last several years I have developed a variety of modeling tools allowing extensive sampling of conformational possibilities of transmembrane GPCRs and their complexes with peptide ligands. This approach allows 3D modeling of receptors belonging to rhodopsin-like family as well as to other families. The most innovative features of the developed approach are as follows:
  1. Sampling involving large movements of transmembrane (TM) helices (as opposed to short molecular dynamics runs)
  2. Accounting for flexibility of the extracellular and intracellular loops that is not addressed by any other approach
  3. Step-by-step validation of modeling results by site-directed mutagenesis
The approach was validated by rationalizing experimental structural and mutagenic results obtained for rhodopsin, angiotensin-type I receptor (AT-1 receptor), CXCR4 receptor and C5a receptor. New efficient constitutively active mutants were predicted for AT-1 receptor and C5a receptor.

Selected Publications:

Nikiforovich GV
, Taylor CM., Marshall, GR, Baranski, TJ. Modeling the possible conformations of the extracellular llops in G-Protein-coupled receptors. Proteins: Structure, Function and Bioinformatics, 2009, in press [PDF]

Nikiforovich, G.V., T.J. Baranski, Structural models for the complex of chemotaxis inhibitory protein of Staphylococcus aureus with the C5a receptor. Biochem. Biophys. Res. Commun., 2009. in press [PDF]

Klco, J. M.; Sen, S.; Hansen, J.L.; Lyngso, C.; Nikiforovich, G. V.; Sheikh, S.P.; Baranski, T. J. Complement factor 5a receptor chimeras reveal the importance of lipid-facing residues in transport competence. FEBS Journal 2009; 276: 2786-2800 [PDF]

Hagemann, I. S.; Miller, D.; Klco, J. M.; Nikiforovich, G. V.; Baranski, T. J. Structure of the complement factor 5a (C5a) receptor/ligand complex studied by disulfide trapping and molecular modeling. J. Biol. Chem. 2008; 283: 7763-7775 [PDF]

Nikiforovich G,
Marshall, GR, Baranski, TJ. Modeling molecular mechanisms of binding of the anaphylatoxin C5a to the C5a receptor. Biochemistry 2008; 47(10):3117-3130. [PDF]

Taylor, CM, Nikiforovich, GV, Marshall, GR. Defining the interface between the C-terminal fragment of α-transducin and photoactivated rhodopsin. Biophys J, 2007; 92:4325-4334. [PDF]

Nikiforovich, GV, Taylor, CM, Marshall, GR. Modeling of the complex between transducin and photoactivated rhodopsin, a prototypical G-protein-coupled receptor. Biochemistry, 2007; 46(16):4734-4744. [PDF]

Matsumoto, ML, Narzinski, K, Nikiforovich, GV, Baranski, TJ. A Comprehensive structure-function map of the intracellular surface of the human C5a receptor II. Elucidation of G protein specificity determinants. J. Biol. Chem., 2007; 282(5):3122-3133. [PDF]

Matsumoto, ML, Narzinski, K, Kiser, PD, Nikiforovich, GV, Baranski, TJ. A Comprehensive structure-function map of the intracellular surface of the human C5a receptor I. Identification of critical residues. J. Biol. Chem., 2007; 282(5):3105-3121. [PDF]

Klco, JM, Nikiforovich, GV, Baranski, TJ. Genetic analysis of the first and third extracellular loops of the C5a receptor reveals an essential WXFG motif in the first loop. J. Biol. Chem., 2006; 281(17):12010-12019. [PDF]

Hagemann, IS, Nikiforovich, GV, Baranski, TJ. Comparison of the retinitis pigmentosa mutations in rhodopsin with a functional map of the C5a receptor. Vision Research, 2006; 46:4519-4531. [PDF]

Nikiforovich, GV, Zhang, M, Yang, Q, Jagadeesh, G, Chen, HC, Hunyady, L, Marshall, GR, and Catt, KJ. Interactions between conserved residues in transmembrane helices 2 and 7 during angiotensin AT1 receptor activation. Chemical Biology & Drug Design, 2006; 68, 239-249. [PDF]

Nikiforovich, GV, Marshall, GR. 3D modeling of the activated states of constitutively active mutants of rhodopsin. Biochemical & Biophysical Research Communications, 2006; 345:430-437 . [PDF]

Nikiforovich GV, Mihalik, B, Catt, KJ, Marshall, GR. Molecular mechanisms of constitutive activity: mutations at position 111 of the angiotensin AT1 receptor. J. Pept. Res., 2005; 66:236-248. [PDF]

Nikiforovich GV, Marshall GR. Modeling flexible loops in the dark-adapted and activated states of rhodopsin, a prototypical G-protein coupled receptor. Bioph. J., 2005; 89:3780-3789. [PDF]

Nikiforovich GV, Marshall GR. 3D model for Meta-II rhodopsin, An activated G-protein-coupled receptor. Biochemistry, 2003; 42:9110-9120. [PDF]

Galaktionov S, Nikiforovich GV, Marshall GR. Ab initio modeling of small, medium and large loops in proteins. Biopolymers (Peptide Science), 2001; 60:153-168. [PDF]

Nikiforovich GV, Marshall GR. 3D Model for TM Region of the AT-1 Receptor in Complex with Angiotensin II Independently Validated by Site-Directed Mutagenesis Data. Biochem. Biophys. Res. Commun. 2001; 286:1204-1211. [PDF]

Nikiforovich GV, Galaktionov S, Balodis J, Marshall GR. Novel approach to computer modeling of seven-helical transmembrane proteins: Current progress in the test case of bacteriorhodopsin. Acta Biochimica Polonica, 2001; 44:53-64. [PDF]

Tseitin VM, Nikiforovich GV. Isolated transmembrane helices arranged across a membrane: computational studies. Protein Engineering 1999; 12(4):305-311. [PDF]

Nikiforovich GV. A Novel Non-Statistical Method for Predicting Breaks in Transmembrane Helices. Protein Engineering 1998; 11:279-283. [PDF]



  Drug Design Based on Computational Studies of Peptides. This scientific endeavor has been my hallmark for many years. 3D models of pharmacophores were obtained for angiotensin, delta-opioid peptides, luliberin, alpha-melanocorticotropin, cholecystokinin, bradykinin, and many other peptides. Virtually all of them have been used as templates for chemical synthesis of biologically active cyclic analogs that are prototypical drug candidates. Currently, I employ this approach for design of various compounds to satisfy continuous needs of academic and industrial communities to design new leads to pharmaceuticals, both peptide and non-peptide.

Selected Publications:

Nikiforovich, G.V. and G.R. Marshall, Computational Approaches in Peptide and Protein Design: An Overview, in Peptide and Protein Design for Biopharmaceutical Applications, K. Jensen, Editor. 2009, John Wiley & Sons: NY.

Sköld, C, Nikiforovich G, Karlén A. Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor. J Mol Graph Model 2008; 26(6):991-1003. [PDF]

Nikiforovich, GV, Marshall, GR, Achilefu, S. Molecular modeling suggests conformational scaffolds specifically targeting five subtypes of somatostatin receptors. Chemical Biology & Drug Design, 2007; 69(3):163-169. [

Zhang, X, Nikiforovich, GV, Marshall, GR. Conformational templates for rational drug design: Flexibility of cyclo(D-Pro1-Ala2-Ala3-Ala4-Ala5) in DMSO solution. J. Med. Chem. 2007; 50(12):2921-2925. [PDF]

Bloch, S, Xu, B, Ye, Y, Liang, K, Nikiforovich, GV, Achilefu, S. Targeting beta-3 integrin using a linear hexapeptide labeled with a near-infrared fluorescent molecular probe. Mol. Pharmaceutics, 2006; 3(5):539-549. [

Våbenø, J, Nikiforovich, GV, Marshall, GR. Insight into the binding mode for cyclopentapeptide antagonists of the CXCR4 receptor. Chemical Biology & Drug Design 2006; 67:346-354. [

Våbenø, J, Nikiforovich, GV, Marshall, GR. A minimalistic 3D pharmacophore model for cyclopentapeptide CXCR4 antagonists. Biopolymers, 2006; 84:459-471. [PDF]

Ye, Y, Li, WP, Anderson, CJ, Kao, GV, Nikiforovich, GV, Achilefu, S. Synthesis and characterization of a macrocyclic near-infrared optical scaffold. J Am Chem Soc, 2003; 125:7766-7767. [PDF]

Johanesson P, Lindeberg G, Johanson A, Nikiforovich GV, Gogoll A, Synnergren B, Le Greves M, Nyberg F, Karlen A, Hallberg A. Vinyl Sulfide Cyclized Analogues of Angiotensin II with High Affinity and Full Agonist Activity at the AT1 Receptor. J. Med. Chem. 2002; 45(9):1767-1777. [


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