Rational Drug Design and Ligand Design Guided by Biophysical Methods

Fragment- and Structure-based Drug Discovery

Professor of Biomedical Sciences Maurizio Pellecchia of the School of Medicine uses a combination of high-field NMR spectroscopy, combinatorial chemistry (HTS by NMR), and fragment-as-structure-based drug design approaches to derive novel pharmacological tools targeting protein-protein interactions. Similar approaches have recently led to the FDA approval of the very first drug targeting a PPI, namely the Bcl-2 antagonist Venetoclax. The laboratory also utilizes advanced biophysical and biochemical approaches including isothermal titration calorimetry measurements to characterize the thermodynamics and kinetics of ligand binding. These approaches have enabled the design of 123C4, a novel potent and selective EphA4 ligand that is being developed for the treatment of ALS.

Along the same lines, Assistant Professor of Biochemistry Jefferson Perry, Assistant Professor of Biochemistry Jikui Song and Associate Professor of Biochemistry Li Fan of the UCR College of Natural and Agricultural Sciences use X-ray crystallography to solve the three-dimensional structure of relevant drug targets in complex with putative ligands. In addition, the laboratories utilize libraries of low molecular weight “fragments” and high-throughput X-ray studies to guide the identification and optimization of lead compounds. These strategies are similar to what has been very recently used to derive the first fragment-based derived inhibitor of a melanoma drug target, leading to the FDA approved agent Vemurafenib.

Bioinformatics, Computational Chemistry, Virtual Docking and Virtual Screening

Scientists at UCR take advantage of advanced computational chemistry approaches accelerate drug discovery and development. Professor of Bioengineering Dimitrios Morikis of the Bourns College of Engineering uses structure-dynamics-interactions-function relations, quasi-dynamic pharmacophore models, and high-throughput computational protocols to design low-molecular mass inhibitors. His laboratory has also developed a translational bioinformatics tool, based on a mathematical model that describes the dynamics of the complement system activation pathways. This tool has the potential for a clinical application in personalized treatment of patients with genetic predisposition for complement-mediated diseases.

Another translational bioinformatics tool for patient-specific drug treatment is based on a probabilistic model for co-receptor selectivity of HIV-1 entry in human cells. Other tools developed by Morikis’ lab involve structural bioinformatics computational frameworks for peptide and protein design, based on molecular dynamics simulations and electrostatic calculations, and pharmacophore-based virtual screening of chemical compounds.

Associate Professor of Chemistry Chia-en Chang develops and applies computational tools to predict and understand protein and drug binding affinities and kinetics. The Chang group uses rigorous free energy calculations to assist/guide structure-based drug design. In addition to how tight a compound can bind, how long a drug can stay and inhibit its target protein, so called residence time, also plays an important role related to in vivo efficacy. Therefore, the Chang group also investigates how ligands can bind and leave fast/slowly using new and existing computational tools that helps researchers design compounds with desired drug binding kinetics.

Pellecchia utilizes computational docking studies, when possible aided by NMR, mutagenesis, or X-ray data, to conduct virtual screening of combinatorial libraries and to guide hit-to-lead optimizations. In addition, the Bioinformatics Core Facility within the Institute for Integrative Genome Biology at UC Riverside provides a tremendous resource for scientists with dedicated hardware and over 500 open source bioinformatics software packages for NGS analysis, comparative genomics, data mining, statistics, molecular modeling, and cheminformatics.

Professor of Bioinformatics Thomas Girke of Botany and Plant Sciences in the College of Natural and Agricultural Sciences focuses on the development of computational data analysis methods for genome biology and small molecule discovery. This includes discovery-oriented data mining projects, as well as algorithm and software development projects for data types from a variety of high-throughput technologies such as next generation sequencing (NGS), genome-wide profiling approaches and drug discovery.

Combinatorial Chemistry

In drug discovery, even minor modifications to a hit compounds can result in dramatic changes in biological efficacy or pharmacokinetic or the agent, making the process of lead optimization daunting. Hence, novel methods that accelerate the synthesis of unique molecules are much needed to enable the rapid exploration of the chemical and biological space of a given compound series. Pellecchia utilizes fragment-based positional scanning approaches, combined with NMR spectroscopy for hit identification, to derive and test large libraries of compounds around a given initial hit or fragment. In addition, the strategy is amenable to the design and synthesis of peptide-mimetics to target PPIs.

Associate Professor of Chemistry Catherine Larsen of the College of Natural and Agricultural Sciences, developed innovative green syntheses in which commercially-available starting materials are converted into nitrogen-containing compounds ranging from heteroaromatics to tetrasubstituted alpha-amino carbon centers. As organometallic catalysts and organocatalysts often enable complementary transformations, both can be used to develop mechanistically distinct reactions that produce functionally diverse compounds with applications for the synthesis of pharmacologically active natural products and/or for the development of novel therapeutics. 

Distinguished Professor of Chemistry Michael Pirrung of the College of Natural and Agricultural Sciences is a pioneer the field of microarrays, which have important biological applications in genomics. He has developed innovative approaches in combinatorial chemistry, using solid-phase synthesis and natural products, and in biological assays using novel optical methods.