Preliminary Work
Fragment screening and HIV therapeutics
Fragment screening is reviewed, providing opportunities for discovery of novel anti-HIV drugs.
Bauman JD, Patel D & Arnold A. Top. Curr. Chem. 317 181-200 (2012)
PubMed PMID: 21972022
PubMedCentral PMCID: PMC3565459
![download](http://www.hivecenter.net/wp-content/uploads/2020/09/download.png)
Identification of HIV-1 Inhibitors Targeting the Nucleocapsid Protein
A high-throughput assay is used to discover drugs that block the action of HIV nucleocapsid
Breuer, S., Chang, M. W., Yuan, J. and Torbett, B. E. J. Med. Chem. 55, 4968-4977 (2012).
![2012Breuer-250](http://www.hivecenter.net/wp-content/uploads/2020/09/2012Breuer-250.jpg)
HIV-1 Reverse Transcriptase Complex with DNA and Nevirapine Reveals Non-nucleoside Inhibition Mechanism
The crystal structures of reverse transcriptase with DNA and two types of inhibitors have been solved. The RT-DNA complex in the crystal could bind either the non-nucleoside inhibitor nevirapine or the nucleoside inhibitor AST-triphosphate, but not both. The structures reveal the complementary roles these different classes of inhibitor play in widely-used anti-AIDS therapies.
K. Das, S. E. Martinez & E. Arnold (2012) Nat. Struct. Mol. Biol. 19, 253-259.
![HIV-1-Reverse-Transcriptase-Complex](http://www.hivecenter.net/wp-content/uploads/2020/09/HIV-1-Reverse-Transcriptase-Complex.png)
Retroviral Intasome Assembly and Inhibition of DNA Strand Transfer
The structure was solved of full-length retroviral integrase from prototype foamy virus in complex with its cognate DNA. The structure shows the organization of retroviral intasome , with an integrase tetramer tightly associated with a pair of viral DNA ends. The structure reveals the extensive protein-DNA and protein-protein interactions involved in retroviral integration, and provides a model for the HIV-1 intasome.
S. Hare, S. S. Gupta, E. Valkov, A. Engelman & P. Cherepanov (2010) Nature 464, 232-236.
![Retroviral-Intasome-Assembly-and-Inhibition-of-DNA-Strand-Transfer](http://www.hivecenter.net/wp-content/uploads/2020/09/Retroviral-Intasome-Assembly-and-Inhibition-of-DNA-Strand-Transfer.png)
A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants.
A combination of structure activity relationships and X-ray crystallography was used to examine non-nucleoside reverse transcriptase inhibitors that are structurally related to rilpivirine to determine their ability to inhibit wildtype reverse transcriptase and several clinically relevant mutants.
![A-comparison-of-the-ability-of-rilpiviri](http://www.hivecenter.net/wp-content/uploads/2020/09/A-comparison-of-the-ability-of-rilpiviri.png)
3D Molecular Models of Whole HIV-1 Virions Generated with CellPACK
Methods for creating 3D models of mature HIV are presented.
![2014Johnson2-250](http://www.hivecenter.net/wp-content/uploads/2020/09/2014Johnson2-250.jpg)
Snapshot of the equilibrium dynamics of a drug bound to HIV-1 reverse transcriptase.
Femtosecond experiments and theory expose the molecular level dynamics of rilpivirine bound to HIV-1 RT.
![download5](http://www.hivecenter.net/wp-content/uploads/2020/09/download5.png)
Fragment-Based Screen Against HIV Protease
Two new inhibitor binding sites were discovered on wild-type HIV protease using fragment-based screening techniques. Protease was cocrystallized or soaked with chemical fragments using five different crystal forms, and 378 data sets were collected. Fragment binding induces a new conformation and crystal form in protease with the active site inhibitor TL-3. This study is the first fragment-based crystallographic screen against HIV protease, revealing two new exosites that stabilize inhibitor binding at the active site.
![download6](http://www.hivecenter.net/wp-content/uploads/2020/09/download6.png)
Structural and Functional Insights into Alphavirus Polyprotein Processing and Pathogenesis
The alphavirus replication machinery consists of four nonstructural proteins produced as a single polyprotein. The structure has been solved of P23 in a precleavage form. The P2/3 cleavage site is located at the base of a narrow cleft and is not readily accessible, and the nsP2 protease active site is over 40 Angstroms away, supporting a regulated, trans cleavage mechanism.
![Structural-and-Functional-Insights-into-Alphavirus-Polyprotein-Processing-and-Pathogenesis](http://www.hivecenter.net/wp-content/uploads/2020/09/Structural-and-Functional-Insights-into-Alphavirus-Polyprotein-Processing-and-Pathogenesis.png)
Theory of binless multi-state free energy estimation with applications to protein-ligand binding.
The paper describes a simplified technique for computing free energies and expectations from multiple ensembles.
Tan Z, Gallicchio E, Lapelosa M, Levy RM. J Chem Phys. 136(14):144102 (2012).
![Theory-of-binless-multi-state-free-energy-estimation](http://www.hivecenter.net/wp-content/uploads/2020/09/Theory-of-binless-multi-state-free-energy-estimation.png)
Small Molecule Regulation of Protein Conformation by Binding in the Flap of HIV Protease
Crystallographic structures of two small indoles reveal a binding site that favors a closed conformation of the HIV protease flaps.
![Small-Molecule-Regulation-of-Protein-Conformation](http://www.hivecenter.net/wp-content/uploads/2020/09/Small-Molecule-Regulation-of-Protein-Conformation.png)