-
Journal of Enzyme Inhibition and... Dec 2019Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations,...
Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant ( < .0001). Amprenavir and ritonavir showed the least decrease, but still significant reduced activity in comparison to the wildtype (4 and 5 folds, respectively, = .0021 and .003, respectively). Nelfinavir and atazanavir were the worst inhibitors against the variant as seen from the IC, with values of 1401 ± 3.0 and 685 ± 3.0 nM, respectively. Thermodynamics data showed less favourable Gibbs free binding energies for the protease inhibitors to the mutant.
Topics: HIV Protease; HIV Protease Inhibitors; HIV-1; Inhibitory Concentration 50; Kinetics; Molecular Docking Simulation; Mutation; Thermodynamics
PubMed: 31409143
DOI: 10.1080/14756366.2019.1636234 -
PloS One 2020The outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus has spread rapidly around the globe during the past 3 months. As the virus...
BACKGROUND
The outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus has spread rapidly around the globe during the past 3 months. As the virus infected cases and mortality rate of this disease is increasing exponentially, scientists and researchers all over the world are relentlessly working to understand this new virus along with possible treatment regimens by discovering active therapeutic agents and vaccines. So, there is an urgent requirement of new and effective medications that can treat the disease caused by SARS-CoV-2.
METHODS AND FINDINGS
We perform the study of drugs that are already available in the market and being used for other diseases to accelerate clinical recovery, in other words repurposing of existing drugs. The vast complexity in drug design and protocols regarding clinical trials often prohibit developing various new drug combinations for this epidemic disease in a limited time. Recently, remarkable improvements in computational power coupled with advancements in Machine Learning (ML) technology have been utilized to revolutionize the drug development process. Consequently, a detailed study using ML for the repurposing of therapeutic agents is urgently required. Here, we report the ML model based on the Naive Bayes algorithm, which has an accuracy of around 73% to predict the drugs that could be used for the treatment of COVID-19. Our study predicts around ten FDA approved commercial drugs that can be used for repurposing. Among all, we found that 3 of the drugs fulfils the criterions well among which the antiretroviral drug Amprenavir (DrugBank ID-DB00701) would probably be the most effective drug based on the selected criterions.
CONCLUSIONS
Our study can help clinical scientists in being more selective in identifying and testing the therapeutic agents for COVID-19 treatment. The ML based approach for drug discovery as reported here can be a futuristic smart drug designing strategy for community applications.
Topics: Algorithms; Bayes Theorem; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Repositioning; Humans; Machine Learning; Molecular Docking Simulation; Pandemics; Pneumonia, Viral; SARS-CoV-2
PubMed: 33180803
DOI: 10.1371/journal.pone.0241543 -
International Journal of Pharmaceutics Jan 2024The primary objective of this study was to enhance the effectiveness of the protease inhibitor antiretroviral drug by designing a novel delivery system using...
The primary objective of this study was to enhance the effectiveness of the protease inhibitor antiretroviral drug by designing a novel delivery system using carboxylated multiwalled carbon nanotubes (COOH-MWCNTs). To achieve this, Fosamprenavir calcium (FPV), a prodrug of amprenavir known for inhibiting the proteolytic cleavage of immature virions, was selected as the protease inhibitor antiretroviral drug, and loaded onto COOH-MWCNTs using a direct loading method. The structural specificity of the drug-loaded MWCNTs, the percent entrapment efficiency, and in vitro drug release were rigorously evaluated for the developed formulation, referred to as FPV-MWCNT. Fourier transform infrared (FTIR) spectroscopy, Field emission scanning electron microscopy (FE-SEM), Raman spectroscopy, and atomic force microscopy (AFM) techniques were employed to confirm the structural integrity and specificity of the FPV-MWCNT formulation. The results demonstrated a remarkable entrapment efficiency of 79.57 ± 0.4 %, indicating the successful loading of FPV onto COOH-MWCNTs. FE-SEM and AFM analyses further confirmed the well-dispersed and elongated structure of the FPV-MWCNT formulation, without any signs of fracture, ensuring the stability and integrity of the drug delivery system. Moreover, particle size analysis revealed an average size of 290.1 nm, firmly establishing the nanoscale range of the formulation, with a zeta potential of 0.230 mV, signifying the system's colloidal stability. In vitro drug release studies conducted in methanolic phosphate buffer saline (PBS) at pH 7.4 and methanolic acetate buffer at pH 5 demonstrated sustained drug release from the FPV-MWCNT formulation. Over a period of 96 h, the formulation exhibited a cumulative drug release of 91.43 ± 2.3 %, showcasing the controlled and sustained release profile. Furthermore, hemolysis studies indicated a notable reduction in the toxicity of both FPV and MWCNT upon conjugation, although the percent hemolysis increased with higher concentrations, suggesting the need for careful consideration of dosage levels. In conclusion, the findings from this study underscore the potential of the FPV-MWCNT formulation as an effective and promising drug-conjugated system for delivering antiretroviral drugs. The successful encapsulation, sustained drug release, and reduced toxicity make FPV-MWCNT a compelling candidate for enhancing the therapeutic efficacy of protease inhibitor antiretroviral drugs in the treatment of HIV. The developed delivery system holds great promise for future advancements in HIV treatment and paves the way for further research and development in the field of drug delivery utilizing carbon nanotube-based systems.
Topics: Humans; Nanotubes, Carbon; Protease Inhibitors; Hemolysis; Drug Delivery Systems; Enzyme Inhibitors; Antiviral Agents; Anti-Infective Agents; HIV Infections
PubMed: 38065344
DOI: 10.1016/j.ijpharm.2023.123678 -
Journal of Molecular Modeling Oct 2021A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on...
A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDA-approved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration.
Topics: Antiviral Agents; COVID-19; Drug Approval; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Protease Inhibitors; SARS-CoV-2; United States; United States Food and Drug Administration; COVID-19 Drug Treatment
PubMed: 34601658
DOI: 10.1007/s00894-021-04923-w -
Biochemical and Biophysical Research... Aug 2021The emergence of multidrug resistant (MDR) HIV strains severely reduces the effectiveness of antiretroviral therapy. Clinical inhibitor darunavir (1) has picomolar...
The emergence of multidrug resistant (MDR) HIV strains severely reduces the effectiveness of antiretroviral therapy. Clinical inhibitor darunavir (1) has picomolar binding affinity for HIV-1 protease (PR), however, drug resistant variants like PR show poor inhibition by 1, despite the presence of only two mutated residues in the inhibitor-binding site. Antiviral inhibitors that target MDR proteases like PR would be valuable as therapeutic agents. Inhibitors 2 and 3 derived from 1 through substitutions at P1, P2 and P2' positions exhibit 3.4- to 500-fold better inhibition than clinical inhibitors for PR with the exception of amprenavir. Crystal structures of PR/2 and PR/3 reveal how these inhibitors target the two active site mutations of PR. The substituted methoxy P2 group of 2 forms new interactions with G48V mutation, while the modified bis-fluoro-benzyl P1 group of 3 forms a halogen interaction with V82S mutation, contributing to improved inhibition of PR.
Topics: Catalytic Domain; Darunavir; Drug Resistance, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Models, Molecular; Point Mutation
PubMed: 34111669
DOI: 10.1016/j.bbrc.2021.05.094