Molecular Modeling

The molecular modeling facility offers several computational biology services such as generation, dynamics and analysis of molecular structures of proteins (including membrane proteins) and nucleic acids, investigating the interaction of protein:ligand, protein:protein, protein:nucleic acid interactions, nucleic acid:ligand complexes, drug discovery including virtual screening against any target, and limited bioinformatics.

The Molecular Modeling Facility was created in 1999 when the Director, Dr. John Trent, was recruited to the Brown Cancer Center. It comprises 6 servers with a total of 550 processors, six graphics workstations, 8 PC/Macs, and, in collaboration with Dataseam, a 3000 processor distributed computing grid. This is in contrast to the original facility, which had three 4-processor servers and two graphics workstations. The Molecular Modeling Facility is an integral part of the structural biology program and works closely with the NMR Facility, biophysicists, molecular biologists, chemists, computer scientists, and biochemists. The core has evolved into a highly collaborative center that provides expertise and resources not available elsewhere in the region. The philosophy of the Facility is rationalization, prediction, and design. The rationalization of experimental data, the prediction of new empirical experiments, and the structure-based drug design of new agents. These aims are being met by maintaining state-of-the-art software and computational resources available to all Cancer Center members. It is the major source of drug discovery at the Brown Cancer Center.

The molecular modeling facility offers several computational biology services such as generation, dynamics and analysis of molecular structures of proteins (including membrane proteins) and nucleic acids, investigating the interaction of protein:ligand, protein:protein, protein:nucleic acid interactions, nucleic acid:ligand complexes, drug discovery including virtual screening against any target, and limited bioinformatics.

The in silico drug discovery effort uses Autodock, DOCK, Surflex, and 3DPL with several databases of over 10,000,000 compounds for virtual screening. We use both core and distributed grid processors. We have successfully virtual screened and tested biologically in over 10 systems where we have obtained inhibitors with activity at less than 10 mM. There are currently more than 20 systems under evaluation.

Molecular modeling software packages in the modeling laboratory include Amber 9.0, 10.0 (Oxford Molecular), complete schrodinger suite of programs, DOCK, Autodock, Surflex. InsightII modules (MSI) Discover, affinity, ludi, biopolymer, and builder, SYBYL, Adv. CoMFA, BioPolymer, CombiLibMaker/Legion, CONCORD, CScore, DISCOtech, FlexS, FlexX, FlexE, FlexX-Pharm, GALAHAD, GASP, Hint!, MOLCAD, QSAR w/ CoMFA, RACHEL, UNITY Base and 3D, Ab initio, semi-empirical, and Poisson-Boltzman electrostatic calculations, GAMESS, MOPAC, Delphi, Molecular Graphics and visualization packages, VMD, Chimera, Grasp (Columbia University), Midas-plus (UCSF) and the DNA analysis program Curves. Other programs include, MC-SYM, Namot, moil-view, molekel and rasmol.

Routine techniques involve ab initio, semi-empirical, empirical (in vacuo, implicit and explicit solvation), QM/MM calculations. Conformational searching: grid searches, simulated annealing, monte carlo, JBW, MC/MD, transition states. Electrostatic surface potentials, partial charges, visualization. Docking. DNA, modified DNA, RNA modeling and analysis and drug design including sequence selectivity, Protein Modeling “sequence to drug design” Structure, homology modeling, ala-scanning, stability, dynamics, protein-ligand, protein-protein, and protein-DNA interactions, membrane proteins, electrostatics, hydration, ion association, docking, virtual screening, pharmacophore generation and searching, NMR structures using state of the art advances in Molecular Modeling, Database searching.

Contacts:
John O. Trent, Director – john.trent@louisville.edu or 502-852-2194

Jonathan M. Maguire, Manager – jon.maguire@louisville.edu or 502 852-3653