Samir Roy, PhD Candidate.

DEPARTMENT OF CHEMISTRY

CHEMISTRY 601/ 603

THEORETICAL SECTION

SPEAKER:            Samir Roy, PhD Candidate

DATE:                     Thursday, November 5, 2009.

TIME:                      3:30 pm

PLACE:                  SB 324

TITLE:                    "Docking Ligands to Homology Model Based Receptors: Potential and    Pitfalls"

ABSTRACT:        

Computer assisted drug design (CADD) techniques are now routinely used for (pre)screening ligand databases. [i] Receptor based CADD techniques, such as ligand docking, display good predictive power if a high quality structure of the target receptor protein is available. However, high quality structures of targeted receptor proteins are frequently not available, even if they have been sequenced. Advances in homology based modeling techniques have made it possible to construct high quality models of sequenced proteins with significant sequence similarity to structurally characterized members of that family.[ii] Such models are often indistinguishable from subsequently obtained x-ray crystal structures of that protein. The use of homology model based receptor structures for ligand docking was traditionally considered an option of last resort. However newer and better methods, software, and assumptions about receptor behavior have made it a worthwhile option for (pre)screening ligands to hitherto inaccessible receptors.[iii]^{, [iv], [v], [vi], [vii], [viii]}

[i] Kroemer RT

Structure-based drug design: docking and scoring.

Curr Protein Pept Sci. 2007, 8(4), 312-28.

[ii] Xiang Z.

Advances in homology protein structure modeling.

Curr Protein Pept Sci. 2006 ,7(3), 217-27.

[iii] Rockey WM, Elcock AH.

Structure selection for protein kinase docking and virtual screening: homology models or crystal structures?

Curr Protein Pept Sci. 2006 , 7(5),  437-57.

[iv] Miguet L, Zervosen A, Gerards T, Pasha FA, Luxen A, Distèche-Nguyen M, Thomas A.

Discovery of new inhibitors of resistant Streptococcus pneumoniae penicillin binding protein (PBP) 2x by structure-based virtual screening.

J Med Chem. 2009, 52(19), 5926-36.

[v] Bisson WH, Koch DC, O'Donnell EF, Khalil SM, Kerkvliet NI, Tanguay RL, Abagyan R, Kolluri SK.

Modeling of the aryl hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands.

J Med Chem. 2009, 52(18), 5635-41.

[vi] 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. 2008, 51(10), 2907-14.

[vii] Mukherjee P, Desai PV, Srivastava A, Tekwani BL, Avery MA.

Probing the structures of leishmanial farnesyl pyrophosphate synthases: homology modeling and docking studies.

J Chem Inf Model. 2008, 48(5), 1026-40.

[viii] Mukherjee P, Pradhan A, Shah F, Tekwani BL, Avery MA.

Structural insights into the Plasmodium falciparum histone deacetylase 1 (PfHDAC-1): A novel target for the development of antimalarial therapy.

Bioorg Med Chem. 2008, 16(9), 5254-65.