A quantitative structure-activity relationship study for structurally diverse HIV-1 protease inhibitors: Contribution of conformational flexibility to inhibitory activity

Journal of Enzyme Inhibition and Medicinal Chemistry
Keigo Gohda

Abstract

In this study, we investigated by linear regression model the SAR data of the 15 HIV-1 protease inhibitors possessing structurally diverse scaffolds. First, a regression model was developed only using the enzyme-inhibitor interaction energy as a term of the model, but did not provide a good correlation with the inhibitory activity (R2 = 0.580 and Q2 = 0.500). Then, we focused on the conformational flexibility of the inhibitors which may represent the diversity of the inhibitors, and added two conformational parameters into the model, respectively: the number of rotatable bonds of ligands (deltaSrot) and the distortion energy of ligands (deltaElig). The regression model by adding deltaElig successfully improved the quality of the model (R2 = 0.771 and Q2 = 0.713) while the model with deltaSrot was unsuccessful. The prediction for a training inhibitor by the deltaElig model also showed good agreement with experimental activity. These results suggest that the conformational flexibility of HIV-1 protease inhibitors directly contributes to the enzyme inhibition.

References

Jul 1, 1987·Journal of Computer-aided Molecular Design·I Pettersson, T Liljefors
Jan 1, 1993·Annual Review of Biochemistry·A Wlodawer, J W Erickson
Apr 1, 1995·Bioorganic & Medicinal Chemistry·M C NicklausG W Milne
Mar 14, 1997·Journal of Medicinal Chemistry·K BäckbroAnders Hallberg
Dec 16, 1997·Journal of Medicinal Chemistry·S W KaldorJ H Tatlock
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·S MunshiL C Kuo
Oct 20, 1998·Journal of Computer-aided Molecular Design·J BoströmT Liljefors
Jan 8, 1999·Journal of Computer-aided Molecular Design·M ViethC L Brooks
Oct 9, 2002·Current Medicinal Chemistry·Hamdy M Abdel-RahmanYoshiaki Kiso
Oct 16, 2002·Trends in Pharmacological Sciences·Luis Menéndez-Arias
Jul 5, 2003·Nature Reviews. Drug Discovery·Yaron Werber
Jan 2, 2004·Nature Reviews. Drug Discovery·Aarti RajaPeter Kirkpatrick
Mar 5, 2004·The New England Journal of Medicine·François Clavel, Allan J Hance
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
May 12, 2004·Current Topics in Medicinal Chemistry·Fátima Rodríguez-Barrios, F Gago
Jun 15, 2004·Current Topics in Medicinal Chemistry·John T Randolph, David A DeGoey
Aug 24, 2004·Current Drug Metabolism·Carmen de Mendoza, Vincent Soriano
Dec 13, 2005·Journal of Medicinal Chemistry·Jenny K EkegrenAnders Hallberg

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Hereditary Sensory Autonomic Neuropathy

Hereditary Sensory Autonomic Neuropathies are a group of inherited neurodegenerative disorders characterized clinically by loss of sensation and autonomic dysfunction. Here is the latest research on these neuropathies.

Glut1 Deficiency

Glut1 deficiency, an autosomal dominant, genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier, is characterized by mental and motor developmental delays and infantile seizures. Follow the latest research on Glut1 deficiency with this feed.

Regulation of Vocal-Motor Plasticity

Dopaminergic projections to the basal ganglia and nucleus accumbens shape the learning and plasticity of motivated behaviors across species including the regulation of vocal-motor plasticity and performance in songbirds. Discover the latest research on the regulation of vocal-motor plasticity here.

Neural Activity: Imaging

Imaging of neural activity in vivo has developed rapidly recently with the advancement of fluorescence microscopy, including new applications using miniaturized microscopes (miniscopes). This feed follows the progress in this growing field.

Nodding Syndrome

Nodding Syndrome is a neurological and epileptiform disorder characterized by psychomotor, mental, and growth retardation. Discover the latest research on Nodding Syndrome here.

LRRK2 & Microtubules

Mutations in the LRRK2 gene are risk-factors for developing Parkinson’s disease (PD). LRRK2 mutations in PD have been shown to enhance its association with microtubules. Here is the latest research.