The National Institute of Diabetes & Digestive & Kidney Diseases

At the Molecular Modeling Unit of LBM we use computational approaches to bridge medicinal chemistry, pharmacology, and experimental biology.

By applying leading techniques in 3-D molecular modeling, bioinformatics, and chemoinformatics, we study the structure-function relationships of biological macromolecules of pharmaceutical interest and investigate their interactions with the cognate ligands. Our primary goal is the rational identification and optimization of low molecular weight compounds capable of modulating their activity to be used as new pharmacological tools or new drug candidates.

To reach our objectives, we operate in strict collaboration with medicinal chemists, molecular pharmacologists, and biologists. G protein coupled receptors (GPCRs) are the targets of our main interest. Other biological systems studied in the laboratory include nuclear hormone receptors (NHR), and cytosolic enzymes.

Stefano Costanzi, Ph.D., is the head of the research unit. He is a medicinal chemist and a molecular modeler with a background in experimental biochemistry. His main interest is the study of the structure, function and ligand interactions of G protein-coupled receptors and soluble proteins, at the interface between biology and chemistry.

His research - covering biochemistry, medicinal chemistry, and molecular modeling - resulted in more than 60 articles in international, peer-reviewed journals (a selection follows).

Engel S, Skoumbourdis AP, Childress J, Neumann S, Deschamps JR, Thomas CJ, Colson AO, Costanzi S, Gershengorn MC A virtual screen for diverse ligands: discovery of selective G protein-coupled receptor antagonists. J Am Chem Soc(130): 5115-23, 2008. [Full Text/Abstract]

Tikhonova IG, Best RB, Engel S, Gershengorn MC, Hummer G, Costanzi S Atomistic insights into rhodopsin activation from a dynamic model. J Am Chem Soc(130): 10141-9, 2008. [Full Text/Abstract]

Houston D, Costanzi S, Jacobson KA, Harden TK Development of selective high affinity antagonists, agonists, and radioligands for the P2Y1 receptor. Comb Chem High Throughput Screen(11): 410-9, 2008. [Full Text/Abstract]

Tikhonova IG, Sum CS, Neumann S, Engel S, Raaka BM, Costanzi S, Gershengorn MC Discovery of novel agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening. J Med Chem(51): 625-33, 2008. [Full Text/Abstract]

Costanzi S, Tikhonova IG, Harden TK, Jacobson KA Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands. J Comput Aided Mol Des, 2008. [Full Text/Abstract]

Costanzi S On the Applicability of GPCR Homology Models to Computer-Aided Drug Discovery: A Comparison between In Silico and Crystal Structures of the beta2-Adrenergic Receptor. J Med Chem(51): 2907-14, 2008. [Full Text/Abstract]

Costanzi S, Neumann S, Gershengorn MC Seven transmembrane-spanning receptors for free fatty acids as therapeutic targets for diabetes mellitus: pharmacological, phylogenetic, and drug discovery aspects. J Biol Chem(283): 16269-73, 2008. [Full Text/Abstract]

Costanzi S, Tikhonova IG, Ohno M, Roh EJ, Joshi BV, Colson AO, Houston D, Maddileti S, Harden TK, Jacobson KA P2Y1 antagonists: combining receptor-based modeling and QSAR for a quantitative prediction of the biological activity based on consensus scoring. J Med Chem(50): 3229-41, 2007. [Full Text/Abstract]

Costanzi S, Ivanov AA, Tikhonova IG, Jacobson KA Structure and Function of G Protein-Coupled Receptors Studied Using Sequence Analysis, Molecular Modeling and Receptor Engineering: Adenosine Receptors. In: Frontiers in Drug Design and Discovery. Caldwell, Rahman, Player, Choudhary, editors. Bentham, 2007. pp.63-79

Deflorian F, Engel S, Colson AO, Raaka BM, Gershengorn MC, Costanzi S Understanding the structural and functional differences between mouse thyrotropin-releasing hormone receptors 1 and 2. Proteins, 2007. [Full Text/Abstract]

Tikhonova IG, Sum CS, Neumann S, Thomas CJ, Raaka BM, Costanzi S, Gershengorn MC Bidirectional, Iterative Approach to the Structural Delineation of the Functional "Chemoprint" in GPR40 for Agonist Recognition. J Med Chem(50): 2981-9, 2007. [Full Text/Abstract]

Sum CS, Tikhonova IG, Neumann S, Engel S, Raaka BM, Costanzi S, Gershengorn MC Identification of residues important for agonist recognition and activation in GPR40. J Biol Chem(282): 29248-55, 2007. [Full Text/Abstract]

Ivanov AA, Ko H, Cosyn L, Maddileti S, Besada P, Fricks I, Costanzi S, Harden TK, Calenbergh SV, Jacobson KA Molecular modeling of the human P2Y2 receptor and design of a selective agonist, 2''-amino-2''-deoxy-2-thiouridine 5''-triphosphate. J Med Chem(50): 1166-76, 2007. [Full Text/Abstract]

Costanzi S, Vincenzetti S, Cristalli G, Vita A Human cytidine deaminase: A three-dimensional homology model of a tetrameric metallo-enzyme inferred from the crystal structure of a distantly related dimeric homologue. J Mol Graph Model (25): 10-6, 2006. [Full Text/Abstract]

Jaschke H, Neumann S, Moore S, Thomas CJ, Colson AO, Costanzi S, Kleinau G, Jiang JK, Paschke R, Raaka BM, Krause G, Gershengorn MC A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). J Biol Chem (281): 9841-4, 2006. [Full Text/Abstract]

Hu J, Jiang J, Costanzi S, Thomas C, Yang W, Feyen JH, Jacobson KA, Spiegel AM A missense mutation in the seven-transmembrane domain of the human Ca2+ receptor converts a negative allosteric modulator into a positive allosteric modulator. J Biol Chem (281): 21558-65, 2006. [Full Text/Abstract]

Jacobson KA, Costanzi S, Kim SK, Roh E, Joshi BV, Tchilibon S, Duong HT, Gao ZG Action of nucleosides and nucleotides at 7 transmembrane-spanning receptors. Nucleosides Nucleotides Nucleic Acids (25): 1425-36, 2006. [Full Text/Abstract]

Jacobson KA, Costanzi S, Joshi BV, Besada P, Shin DH, Ko H, Ivanov AA, Mamedova L Agonists and antagonists for P2 receptors. Novartis Found Symp (276): 58-68; discussion 68-72, 107-12, 275-81, 2006. [Full Text/Abstract]

Ivanov AA, Costanzi S, Jacobson KA Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling. J Comput Aided Mol Des (20): 417-26, 2006. [Full Text/Abstract]

Moore S, Jaeschke H, Kleinau G, Neumann S, Costanzi S, Jiang JK, Childress J, Raaka BM, Colson A, Paschke R, Krause G, Thomas CJ, Gershengorn MC Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: structure-activity relationships and selective binding patterns. J Med Chem (49): 3888-96, 2006. [Full Text/Abstract]

Jacobson KA, Costanzi S, Ivanov AA, Tchilibon S, Besada P, Gao ZG, Maddileti S, Harden TK Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5''-triphosphate analogues at the human P2Y2 and P2Y4 receptors. Biochem Pharmacol (71): 540-9, 2006. [Full Text/Abstract]

Besada P, Shin DH, Costanzi S, Ko H, Mathe C, Gagneron J, Gosselin G, Maddileti S, Harden TK, Jacobson KA Structure-activity relationships of uridine 5''-diphosphate analogues at the human P2Y6 receptor. J Med Chem (49): 5532-43, 2006. [Full Text/Abstract]

Costanzi S, Joshi BV, Maddileti S, Mamedova L, Gonzalez-Moa MJ, Marquez VE, Harden TK, Jacobson KA Human P2Y(6) receptor: molecular modeling leads to the rational design of a novel agonist based on a unique conformational preference. J Med Chem (48): 8108-11, 2005. [Full Text/Abstract]

Besada P, Mamedova L, Thomas CJ, Costanzi S, Jacobson KA Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality. Org Biomol Chem (3): 2016-25, 2005. [Full Text/Abstract]

Cristalli G, Podda GM, Costanzi S, Lambertucci C, Lecchi A, Vittori S, Volpini R, Zighetti ML, Cattaneo M Effects of 5''-phosphate derivatives of 2-hexynyl adenosine and 2-phenylethynyl adenosine on responses of human platelets mediated by P2Y receptors. J Med Chem (48): 2763-6, 2005. [Full Text/Abstract]

Jacobson KA, Mamedova L, Joshi BV, Besada P, Costanzi S Molecular recognition at adenine nucleotide (P2) receptors in platelets. Semin Thromb Hemost (31): 205-16, 2005. [Full Text/Abstract]

Costanzi S, Lambertucci C, Portino FR, Volpini R, Vittori S, Cristalli G Ring opening reactions: synthesis of AICAR analogs as potential antimetabolite agents. Nucleosides Nucleotides Nucleic Acids (24): 415-8, 2005. [Full Text/Abstract]

Costanzi S, Mamedova L, Gao ZG, Jacobson KA Architecture of P2Y nucleotide receptors: structural comparison based on sequence analysis, mutagenesis, and homology modeling. J Med Chem (47): 5393-404, 2004. [Full Text/Abstract]

Ohno M, Costanzi S, Kim HS, Kempeneers V, Vastmans K, Herdewijn P, Maddileti S, Gao ZG, Harden TK, Jacobson KA Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and l-alpha-threofuranosyl ring systems: interactions with P2Y receptors. Bioorg Med Chem (12): 5619-30, 2004. [Full Text/Abstract]

Jacobson KA, Kim SK, Costanzi S, Gao ZG Purine receptors: gpcr structure and agonist design. Mol Interv (4): 337-47, 2004. [Full Text/Abstract]

Costanzi S, Lambertucci C, Vittori S, Volpini R, Cristalli G 2- and 8-alkynyladenosines: conformational studies and docking to human adenosine A3 receptor can explain their different biological behavior. J Mol Graph Model (21): 253-62, 2003. [Full Text/Abstract]

Costanzi S, Vincenzetti S, Vita A, Lambertucci C, Taffi S, Volpini R, Vittori S, Cristalli G Human cytidine deaminase: understanding the catalytic mechanism. Nucleosides Nucleotides Nucleic Acids (22): 1539-43, 2003. [Full Text/Abstract]

Vincenzetti S, De Sanctis G, Costanzi S, Cristalli G, Mariani P, Mei G, Neuhard J, Natalini P, Polzonetti V, Vita A Functional properties of subunit interactions in human cytidine deaminase. Protein Eng (16): 1055-61, 2003. [Full Text/Abstract]