Pharmacophore Development and Docking Studies of the HIV‐1 Integrase Inhibitors Derived from <i>N</i>‐methylpyrimidones, Dihydroxypyrimidines, and Bicyclic Pyrimidinones

Telvekar, Vikas N.; Patel, Kavitkumar

doi:10.1111/j.1747-0285.2011.01130.x

Cited by 13 publications

(4 citation statements)

References 44 publications

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“…Ligand-based drug design approaches like quantitative structure-activity relationship (QSAR) and pharmacophore modeling have established their effectiveness in designing/envisaging the action of new molecules and in searching chemical databases to detect novel lead scaffolds in the absence of target receptor 3D structure [97][98][99]. QSAR and quantitative structure-property relationship approach developed a mathematical model for biological activity employing numerous structural and functional properties [100][101][102].…”

Section: Computer-aided Drug Design/repurposingmentioning

confidence: 99%

Therapeutic Inhibitors: Natural Product Options through Computer-Aided Drug Design

Ejiofor¹,

Ekeomodi²,

Elomeme³

et al. 2022

Drug Repurposing - Molecular Aspects and Therapeutic Applications

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Drug repurposing involves reusing an active pharmaceutical ingredient that is already in the market and drugs that were unsuccessful in their clinical phases of development for a new indication. It has numerous benefits in drug development. Therapeutic inhibitors are agents that could be of synthetic or natural source with the ability to trigger the down-regulation of an enzyme or protein, thereby inducing therapeutic effect(s). Researchers have embraced synthetic methods in searching for therapeutic molecules through structural activity relationships and other means in the past and recent times. Despite these synthetic drugs, the morbidity and mortality rate of ailment and disease affecting humanity remains overwhelming. Research has shown that solutions to these challenges can be attempted through drug repurposing. In the past, natural products in raw forms have been utilized in traditional, complementary medicine to manage and treat diseases and illnesses, as there are molecules in use today as drugs, which originated from plants and other natural sources. Studies on natural products have led to diverse natural product databases that can serve as a source of repurposing agents. There are also databases for protein and enzymes of human origin, which have an enormous role in the in-silico drug repurposing approach.

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Section: Computer-aided Drug Design/repurposingmentioning

confidence: 99%

Therapeutic Inhibitors: Natural Product Options through Computer-Aided Drug Design

Ejiofor¹,

Ekeomodi²,

Elomeme³

et al. 2022

Drug Repurposing - Molecular Aspects and Therapeutic Applications

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“…The computational methods in drug discovery collectively termed pharmacoinformatics, includes structure activity relationship (SAR), pharmacophore, virtual screening and molecular docking and these have proven their pivotal role in the pharmaceutical industry for lead identification and optimization. Several research groups worldwide identified integrase inhibitors [11][12][13][14][15][16][17] using pharmacoinformatics approaches for potential application for HIV therapy. Consistent with the objective of developing new potent and less toxic integrase inhibitors the current research explores the binding preferences of the inhibitory molecules of HIV integrase in terms of space modelling study and virtual screening along with molecular docking and molecular dynamics.…”

Section: Introductionmentioning

confidence: 99%

Structural requirements for potential HIV-integrase inhibitors identified using pharmacophore-based virtual screening and molecular dynamics studies

Islam

Pillay

2016

Mol. BioSyst.

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Acquired immunodeficiency syndrome (AIDS) is a life-threatening disease which is a collection of symptoms and infections caused by a retrovirus, human immunodeficiency virus (HIV). There is currently no curative treatment and therapy is reliant on the use of existing anti-retroviral drugs. Pharmacoinformatics approaches have already proven their pivotal role in the pharmaceutical industry for lead identification and optimization. In the current study, we analysed the binding preferences and inhibitory activity of HIV-integrase inhibitors using pharmacoinformatics. A set of 30 compounds were selected as the training set of a total 540 molecules for pharmacophore model generation. The final model was validated by statistical parameters and further used for virtual screening. The best mapped model (R = 0.940, rmsd = 2.847, Q 2 = 0.912, se = 0.498, R 2 pred = 0.847 and r 2 m (test) = 0.636) explained that two hydrogen bond acceptor and one aromatic ring features were crucial for the inhibition of HIV-integrase. From virtual screening, initial hits were sorted using a number of parameters and finally two compounds were proposed as promising HIV-integrase inhibitors. Drug-likeness properties of the final screened compounds were compared to FDA approved HIV-integrase inhibitors. HIV-integrase structure in complex with the most active and final screened compounds were subjected to 50ns molecular dynamics (MD) simulation studies to check comparative stability of the complexes. The study suggested that the screened compounds might be promising HIV-integrase inhibitors. The new chemical entities obtained from the NCI database will be subjected to experimental studies to confirm potential inhibition of HIV integrase. IntroductionHuman immunodeficiency virus (HIV) is the aetiological agent of acquired immunodeficiency syndrome (AIDS) which destroys the immune system of the body leaving the victim vulnerable to infections, malignancies and neurological disorder. Owing to its rapid spread it has become a serious global threat and there is no curative treatment for this fatal disease. According to statistics by World Health Organization (WHO), a total of 37.20 million people are living with AIDS and 1.70 million people died in 2013 alone.Currently, there are 3 categories of therapeutic anti-HIV drugs based on their inhibitory mechanisms 1 and these include nucleoside reverse transcriptase inhibitors (NRTIs) 2 , non-nucleoside reverse transcriptase inhibitors (NNRTIs) 3 , and protease inhibitors (PIs) 4,5 . To date the highly active antiretroviral therapy (HAART) 6 which is combined therapy using the above classes of inhibitors is widely used for patients with advance infection but has failed to eradicate the virus. HAART is intended to slow down viral replication and lower the patient's total burden of HIV infection, but this treatment is not entirely cost effective and is often out of reach of people worldwide. The genome of the HIV encodes for three enzymes viz. the protease, reverse transcriptase and integrase. The integrase...

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“…Integrase (IN), a 32 kDa protein in Human Immunodeficiency Virus (HIV), is a promising anti-HIV target and several classes of inhibitors have been reported (Gupta, Roy & Garg 2009; Plewe et al 2009; Cheng, Zhang & Fu 2010; Tanis et al 2010; Johnson et al 2011; Sharma et al 2011; Telvekar & Patel 2011). IN active-site-directed strand transfer inhibitors, Raltegravir, Elvitegravir and Dolutegravir have been approved by Food and Drug Administration for anti-retroviral therapy (http://aidsinfo.nih.gov/guidelines; Summa et al 2008; Volberding & Deeks 2010).…”

Section: Introductionmentioning

confidence: 99%

The conformational feasibility for the formation of reaching dimer in ASV and HIV integrase: a molecular dynamics study

Balasubramanian

Rangarajan

Bojja

et al. 2016

Journal of Biomolecular Structure and Dynamics

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Retroviral integrases are reported to form alternate dimer assemblies like the core-core dimer and reaching dimer. The core-core dimer is stabilized predominantly by an extensive interface between two catalytic core domains. The reaching dimer is stabilized by N-terminal domains (NTD) that reach to form intermolecular interfaces with the other subunit’s core and C-terminal domains (CTD), as well as CTD-CTD interactions. In this study, molecular dynamics (MD), Brownian dynamics (BD) simulations, and free energy analyses, were performed to elucidate determinants for the stability of the reaching dimer forms of full-length ASV and HIV IN, and to examine the role of the C-tails (the last ~16–18 residues at the C-termini) in their structural dynamics. The dynamics of an HIV reaching dimer derived from SAXS and protein crosslinking data, was compared with the dynamics of a core-core dimer model derived from combining the crystal structures of two-domain fragments. The results showed that the core domains in the ASV reaching dimer express free dynamics, whereas those in the HIV reaching dimer are highly stable. Brownian dynamics simulations suggest a higher rate of association for the HIV core-core dimer than the reaching dimer. The predicted stability of these dimers was therefore ranked in the following order: ASV reaching dimer

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Pharmacophore Development and Docking Studies of the HIV‐1 Integrase Inhibitors Derived from N‐methylpyrimidones, Dihydroxypyrimidines, and Bicyclic Pyrimidinones

Cited by 13 publications

References 44 publications

Therapeutic Inhibitors: Natural Product Options through Computer-Aided Drug Design

Therapeutic Inhibitors: Natural Product Options through Computer-Aided Drug Design

Structural requirements for potential HIV-integrase inhibitors identified using pharmacophore-based virtual screening and molecular dynamics studies

The conformational feasibility for the formation of reaching dimer in ASV and HIV integrase: a molecular dynamics study

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