The role of weak interactions in evaluation of inhibitory potential of Indinavir as an HIV protease inhibitor and its comparison with innovative drug candidates

Designing and employing enzyme inhibitors against viral enzymes is one of the innovative and efficient approaches to treating viral diseases. These inhibitors can disrupt the viral replication cycle by deactivating vital enzymes, thereby curbing the spread of viral infections by reducing their popul...

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Vydáno v:	Computers in biology and medicine Ročník 187; s. 109675
Hlavní autoři:	Yoosefian, Mehdi, Sabaghian, Hanieh
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Ltd 01.03.2025 Elsevier Limited
Témata:	Acquired immune deficiency syndrome Acquired immunodeficiency syndrome (AIDS) AIDS Analogs Antiretroviral drugs Atoms & subatomic particles Binding Sites Bioavailability Design Design improvements Drug design Drug development Drugs Energy Enzymes FDA approval Genetic algorithms HIV HIV Protease - chemistry HIV Protease - metabolism HIV protease enzyme HIV Protease Inhibitors - chemistry HIV Protease Inhibitors - pharmacokinetics HIV Protease Inhibitors - pharmacology Human immunodeficiency virus Humans Immune system Indinavir Indinavir - analogs & derivatives Indinavir - chemistry Indinavir - pharmacokinetics Indinavir - pharmacology Internal Medicine Ligands Molecular docking Molecular Docking Simulation Molecular dynamics Molecular Dynamics Simulation Optimization Other Performance evaluation Pharmacokinetics Protease Protease inhibitors Proteinase inhibitors Proteins Quantum physics Simulation Toxicity Viral diseases United States > US Drug design Acquired immunodeficiency syndrome (AIDS) Pharmacokinetics HIV protease enzyme Indinavir
ISSN:	0010-4825, 1879-0534, 1879-0534
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Shrnutí:	Designing and employing enzyme inhibitors against viral enzymes is one of the innovative and efficient approaches to treating viral diseases. These inhibitors can disrupt the viral replication cycle by deactivating vital enzymes, thereby curbing the spread of viral infections by reducing their population. So far, inhibitors have been designed, validated, and introduced for these enzymes. In this study, we designed the drug Indinavir and 20 analogs using Hartree-Fock and DFT methods to enhance the design of more potent protease enzyme inhibitors. Frequency calculations were performed at similar computational levels for all examined drugs and their designed analogs, revealing no negative frequencies. The Pharmacokinetics of the inhibitors were assessed, and inhibitors were screened, with those exhibiting minimal toxicity introduced as drug candidates for further evaluation. The best binding mode of Indinavir and the designed drugs at the protein binding site were determined using molecular docking studies. For the IND20 inhibitor with the best binding mode, an energy of −13.03 (kcal/mol) was reported. Finally, molecular dynamics simulations were conducted to evaluate the inhibitory mechanism of the recommended inhibitor on the protease enzyme. The relevant analyses during the simulation period showed that the designed drug IND20 exhibited better performance in inhibiting the HIV-1 protease enzyme compared to Indinavir. [Display omitted] •The role of weak interactions such as hydrogen bonding in inhibitory ability have been investigated completely.•The study focuses on the design and validation of protease enzyme inhibitors, highlighting Indinavir and its analogs.•Pharmacokinetics was assessed, and minimally toxic inhibitors were selected as candidates for further drug development.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0010-4825 1879-0534 1879-0534
DOI:	10.1016/j.compbiomed.2025.109675