Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Establishment of selective antiviral chemotherapy has achieved dramatic improvement of the prognosis of several viral infections. It has been considered for a long time that, unlike bacterial infections, viral diseases cannot be successfully treated with chemotherapeutic agents, since viral replication mostly depends on the host-cellular machinery. In fact, some compounds were reported to inhibit viral replication even in the 1950s and 1960s, yet they were also quite toxic to the host cells. The first antiviral compound that strongly inhibits viral replication without affecting the uninfected cells is the anti-herpes agent acyclovir (ACV), which was discovered in the 1970s. Furthermore, in the 1980s, the world-wide epidemic of AIDS caused by human immunodeficiency virus type 1 (HIV-1) infection has dramatically accelerated the development of new antiviral agents. At present, most of the effective antivirals are targeted at virus-specific enzymes, such as ACV for herpes virus thymidine kinase, zidovudine for HIV-1 reverse transcriptase, squinavir for HIV-1 protease, and oseltamivir for neuraminidase of influenza virus. These agents can be administered systemically without serious side effects. However, several drawbacks, including delayed toxicity and drug-resistance, are associated with long-term treatment with several antiviral agents mostly in highly active antiretroviral therapy for HIV-1 infection. Thus, it seems still mandatory to continue the search for more effective and less toxic compounds against various viral infections.
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PMID:[Advances in antiviral chemotherapy]. 1630 32

We report the development and validation of a novel suite of programs, FITTED 1.0, for the docking of flexible ligands into flexible proteins. This docking tool is unique in that it can deal with both the flexibility of macromolecules (side chains and main chains) and the presence of bridging water molecules while treating protein/ligand complexes as realistically dynamic systems. This software relies on a genetic algorithm to account for the flexibility of the two molecules as well as the location of bridging water molecules. In addition, FITTED 1.0 features a novel application of a switching function to retain or displace key water molecules from the protein-ligand complexes. Two independent modules, ProCESS and SMART, were developed to set up the proteins and the ligands prior to the docking stage. Validation of the accuracy of the software was achieved via the application of FITTED 1.0 to the docking of inhibitors of HIV-1 protease, thymidine kinase, trypsin, factor Xa, and MMP to their respective proteins.
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PMID:Docking ligands into flexible and solvated macromolecules. 1. Development and validation of FITTED 1.0. 1730 29

The identification of small molecules with selective bioactivity, whether intended as potential therapeutics or as tools for experimental research, is central to progress in medicine and in the life sciences. To facilitate such study, we have developed a ligand-based program well-suited for effective screening of large compound collections. This package, MED-SuMoLig, combines a SMARTS-driven substructure search aiming at 3D pharmacophore profiling and computation of the local atomic density of the compared molecules. The screening utility was then investigated using 52 diverse active molecules (against CDK2, Factor Xa, HIV-1 protease, neuraminidase, ribonuclease A, and thymidine kinase) merged to a library of about 40,000 putative inactive (druglike) compounds. In all cases, the program recovered more than half of the actives in the top 3% of the screened library. We also compared the performance of MED-SuMoLig with that of ChemMine or of ROCS and found that MED-SuMoLig outperformed both methods for CDK2 and Factor Xa in terms of enrichment rates or performed equally well for the other targets.
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PMID:MED-SuMoLig: a new ligand-based screening tool for efficient scaffold hopping. 1747 21