In recent years, the availability of high resolution structures of enzyme-inhibitor complexes has led to an increased understanding of molecular interactions. Using this structural information, computer-based approaches help identify or design ligands that posses good steric and chemical complementarity to various sites on the enzyme. This process is referred to as """"""""structure-based molecular design"""""""". The long term objective of this work is to develop a method to computationally screen and evaluate ligands as potential lead compounds. We are seeking a method that is rapid and reasonably accurate. The DOCK suite of programs, developed by the Kuntz group, identifies and characterizes sites on a receptor or protein for inhibitor binding; orients (a database of) molecules; and evaluates these molecules for goodness of fit. We are applying the structure-based methodology to identify inhibitors of the enzyme inosine monophosphate dehydrogenase (impdh), which plays a key role in growth of several parasites. MidasPlus is used to examine different conformations and orientations of the ligand and enzyme. MidasPlus is also used to display and select site points (referred to as DOCK spheres) within the enzyme active site. A MidasPlus delegate, VIEWDOCK, has been particularly important in examining output of DOCK jobs and in selecting compounds for testing in the parasite project. We expect VIEWDOCK to continue to be useful in this manner in other similar projects examining DOCK output.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-23
Application #
6347926
Study Section
Project Start
2000-07-01
Project End
2001-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
23
Fiscal Year
2000
Total Cost
$818
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2018) Relaxation of structural constraints during Amicyanin unfolding. J Inorg Biochem 179:135-145
Alamo, Lorenzo; Pinto, Antonio; Sulbarán, Guidenn et al. (2018) Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease. Biophys Rev 10:1465-1477
Viswanath, Shruthi; Chemmama, Ilan E; Cimermancic, Peter et al. (2017) Assessing Exhaustiveness of Stochastic Sampling for Integrative Modeling of Macromolecular Structures. Biophys J 113:2344-2353
Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219
Portioli, Corinne; Bovi, Michele; Benati, Donatella et al. (2017) Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J Biomed Mater Res A 105:847-858
Alamo, Lorenzo; Koubassova, Natalia; Pinto, Antonio et al. (2017) Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. Biophys Rev 9:461-480
Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A et al. (2017) Enhanced potency of bivalent small molecule gp41 inhibitors. Bioorg Med Chem 25:408-420
Sato, Daisuke; Shannon, Thomas R; Bers, Donald M (2016) Sarcoplasmic Reticulum Structure and Functional Properties that Promote Long-Lasting Calcium Sparks. Biophys J 110:382-390
Towse, Clare-Louise; Rysavy, Steven J; Vulovic, Ivan M et al. (2016) New Dynamic Rotamer Libraries: Data-Driven Analysis of Side-Chain Conformational Propensities. Structure 24:187-199

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