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1.  Hydrocarbon-Stapled Peptides: Principles, Practice, and Progress 
Journal of Medicinal Chemistry  2014;57(15):6275-6288.
Protein structure underlies essential biological processes and provides a blueprint for molecular mimicry that drives drug discovery. Although small molecules represent the lion’s share of agents that target proteins for therapeutic benefit, there remains no substitute for the natural properties of proteins and their peptide subunits in the majority of biological contexts. The peptide α-helix represents a common structural motif that mediates communication between signaling proteins. Because peptides can lose their shape when taken out of context, developing chemical interventions to stabilize their bioactive structure remains an active area of research. The all-hydrocarbon staple has emerged as one such solution, conferring α-helical structure, protease resistance, cellular penetrance, and biological activity upon successful incorporation of a series of design and application principles. Here, we describe our more than decade-long experience in developing stapled peptides as biomedical research tools and prototype therapeutics, highlighting lessons learned, pitfalls to avoid, and keys to success.
PMCID: PMC4136684  PMID: 24601557
2.  The Current State of Drug Discovery and a Potential Role for NMR Metabolomics 
Journal of Medicinal Chemistry  2014;57(14):5860-5870.
The pharmaceutical industry has significantly contributed to improving human health. Drugs have been attributed to both increasing life expectancy and decreasing health care costs. Unfortunately, there has been a recent decline in the creativity and productivity of the pharmaceutical industry. This is a complex issue with many contributing factors resulting from the numerous mergers, increase in out-sourcing, and the heavy dependency on high-throughput screening (HTS). While a simple solution to such a complex problem is unrealistic and highly unlikely, the inclusion of metabolomics as a routine component of the drug discovery process may provide some solutions to these problems. Specifically, as the binding affinity of a chemical lead is evolved during the iterative structure-based drug design process, metabolomics can provide feedback on the selectivity and the in vivo mechanism of action. Similarly, metabolomics can be used to evaluate and validate HTS leads. In effect, metabolomics can be used to eliminate compounds with potential efficacy and side effect problems while prioritizing well-behaved leads with druglike characteristics.
PMCID: PMC4324437  PMID: 24588729
3.  Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic Approaches 
Journal of Medicinal Chemistry  2013;56(20):7719-7726.
Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of molecular targets from phenotypic approaches can be a way to identify potential new drug targets.
PMCID: PMC3954685  PMID: 24015767
4.  Inhibiting the HIV Integration Process: Past, Present, and the Future 
Journal of Medicinal Chemistry  2013;57(3):539-566.
HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.
PMCID: PMC3926363  PMID: 24025027
5.  Rational Approaches to Improving Selectivity in Drug Design 
Journal of Medicinal Chemistry  2012;55(4):1424-1444.
PMCID: PMC3285144  PMID: 22239221
7.  A Medicinal Chemist’s Guide to Molecular Interactions 
Journal of Medicinal Chemistry  2010;53(14):5061-5084.
PMCID: PMC2905122  PMID: 20345171
8.  Organometallic Anticancer Compounds 
PMCID: PMC3018145  PMID: 21077686
10.  Attenuating Staphylococcus aureus Virulence Gene Regulation: A Medicinal Chemistry Perspective 
Journal of Medicinal Chemistry  2013;56(4):1389-1404.
Virulence gene expression in Staphylococcus aureus is tightly regulated by intricate networks of transcriptional regulators and two-component signal transduction systems. There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models. In this Perspective, we will provide insights into medicinal chemistry strategies for the development of chemical reagents that have the capacity to inhibit staphylococcal virulence expression. These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA–DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators. We discuss the potential of specific examples of antivirulence agents for the management and treatment of staphylococcal infections.
PMCID: PMC3585718  PMID: 23294220

Results 1-10 (10)