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Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance.
Chem Commun (Camb)
October 2022
Departments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological and drug-resistance profiles. Our X-ray structural studies of darunavir and other designed inhibitors from our laboratories led us to create a variety of inhibitors incorporating fused ring polycyclic ethers and aromatic heterocycles to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease as well as van der Waals interactions with residues in the S2 and S2' subsites. We have also incorporated specific functionalities to enhance van der Waals interactions in the S1 and S1' subsites.
View Article and Find Full Text PDFPocket-to-Lead: Structure-Based Design of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocket as a Template.
J Med Chem
April 2022
Shionogi Pharmaceutical Research Center, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
A novel strategy for lead identification that we have dubbed the "Pocket-to-Lead" strategy is demonstrated using HIV-1 protease as a model target. Sometimes, it is difficult to obtain hit compounds because of the difficulties in satisfying the complex pharmacophoric features. In this study, a virtual fragment hit which does not match all of the pharmacophore features but has key interactions and vectors that could grow into remaining pharmacophore features was optimized .
View Article and Find Full Text PDFNature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors.
Asian J Org Chem
August 2018
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907 (USA).
We have developed a conceptually new generation of non-peptidic HIV-1 protease inhibitors incorporating novel structural templates inspired by nature. This has resulted in protease inhibitors with exceptional potency and excellent pharmacological and drug-resistance profiles. The design of a stereochemically defined -tetrahydrofuran (-THF) scaffold followed by modifications to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease led to darunavir, the first clinically approved drug for treatment of drug resistant HIV.
View Article and Find Full Text PDFTherapeutic potential of coumarins as antiviral agents.
Eur J Med Chem
November 2016
Maharishi Arvind College of Pharmacy, Ambabari, Jaipur 302 039, India.
Coumarins have received a considerable attention in the last three decades as a lead structures for the discovery of orally bioavailable non-peptidic antiviral agents. A lot of structurally diverse coumarins analogues were found to display remarkable array of affinity with the different molecular targets for antiviral agents and slight modifications around the central motif result in pronounced changes in its antiviral spectrum. This manuscript thoroughly reviews the design, discovery and structure-activity relationship studies of the coumarin analogues as antiviral agents focusing mainly on lead optimization and its development into clinical candidates.
View Article and Find Full Text PDFA critical review of properties of darunavir and analytical methods for its determination.
Crit Rev Anal Chem
July 2015
a Drugs and Medicines Quality Control Laboratory , School of Pharmaceutical Sciences University Estadual Paulista, Araraquara , Brazil.
Darunavir is a synthetic non-peptidic protease inhibitor that has been shown to be extremely potent against wild-type HIV, and it is an important component of highly active antiretroviral treatment (HAART), which is considered as one of the most significant advances in the field of HIV therapy. However, there are some concerns about darunavir quality control. Darunavir shows pseudo-polymorphism: in different ambient conditions one pseudo-polymorphic form can change to another.
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