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

Comparative Molecular Field Analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm (Cramer, R.D.; et al. (1988), J. Am. Chem. Soc., 110, 5959-5967), correlates variations in the (experimental) biological activity with 3D variance in the steric and electrostatic field of modeled compounds. Of general interest to the drug design area is the interpretation of CoMFA results, in order to gain maximum benefit from an established 3D-QSAR model. CoMFA studies report results using the standard deviation (stdev) times(*) coefficient (beta) field and its contributions to make SAR statements. This field is the scalar product of the absolute stdev of the CoMFA field at a lattice point and the QSAR equation coefficient (beta) at the same point. Negative beta values yield detrimental contributions, while positive beta values are considered beneficial. The QSAR equation is based on actual field values, therefore both positive and negative field values can have beneficial effect to the target property (Y), depending on the sign of beta. The results of a CoMFA model on 59 HIV-1 protease (HIV-PR) inhibitors (Waller, C.L.; et al. (1993), J. Med. Chem., 36, 4152-4160) were compared with the HIV-PR crystal structure to analyze the correspondence between CoMFA fields and ligand binding regions in the enzyme. Local steric and electrostatic interactions were analyzed in terms of various field values and beta coefficients. While redundant for some regions, other field contours besides stdev* beta bring additional information. Using this method, we observed a unique region with negative beta values for the electrostatic field (based on a -1 charged probe) located opposite of the scissile bond, between P1 and P1', where steric stdev* beta values are positive. Four hydrophobic residues in the HIV-PR crystal delimit the region, which is suggested as a new potential hydrophobic binding site for the inhibitors. The same region was confirmed using the stdev* beta contours of a HINT (Kellogg, G.; et al. (1991), J. Comput.-Aided Mol. Design, 5, 545-552) calculation on the same model. The steric, electrostatic and lipophilic fields of the CoMFA and HINT models are presented in various forms, and the information extracted is detailed.
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PMID:3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III. Interpretation of CoMFA results. 757 6

This article will discuss the motivations, technologies, and future directions of computational automated docking in the context of the structure-based rational design of HIV-1 protease inhibitors. Docking simulations are widely used for screening of compound libraries to identify new drug leads, employing a simple model for rapid testing of thousands of compounds. Docking simulations are also useful for lead enhancement, using more detailed models to analyze the atomic interactions between inhibitors and target macromolecules. Major advances have been reported in the development of empirical force fields, which now allow assessment of relative binding strength and drug specificity, and extensions of automated docking techniques allow de novo drug design.
SAR QSAR Environ Res 1998
PMID:Automated docking and the search for HIV protease inhibitors. 952 77

Identification and size characterization of surface pockets and occluded cavities are initial steps in protein structure-based ligand design. A new program, CAST, for automatically locating and measuring protein pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings, and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. CAST analysis of over 100 proteins has been carried out; proteins examined include a set of 51 monomeric enzyme-ligand structures, several elastase-inhibitor complexes, the FK506 binding protein, 30 HIV-1 protease-inhibitor complexes, and a number of small and large protein inhibitors. Medium-sized globular proteins typically have 10-20 pockets/cavities. Most often, binding sites are pockets with 1-2 mouth openings; much less frequently they are cavities. Ligand binding pockets vary widely in size, most within the range 10(2)-10(3)A3. Statistical analysis reveals that the number of pockets and cavities is correlated with protein size, but there is no correlation between the size of the protein and the size of binding sites. Most frequently, the largest pocket/cavity is the active site, but there are a number of instructive exceptions. Ligand volume and binding site volume are somewhat correlated when binding site volume is < or =700 A3, but the ligand seldom occupies the entire site. Auxiliary pockets near the active site have been suggested as additional binding surface for designed ligands (Mattos C et al., 1994, Nat Struct Biol 1:55-58). Analysis of elastase-inhibitor complexes suggests that CAST can identify ancillary pockets suitable for recruitment in ligand design strategies. Analysis of the FK506 binding protein, and of compounds developed in SAR by NMR (Shuker SB et al., 1996, Science 274:1531-1534), indicates that CAST pocket computation may provide a priori identification of target proteins for linked-fragment design. CAST analysis of 30 HIV-1 protease-inhibitor complexes shows that the flexible active site pocket can vary over a range of 853-1,566 A3, and that there are two pockets near or adjoining the active site that may be recruited for ligand design.
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PMID:Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design. 976 70

The synthesis and the SAR study of novel pseudo symmetric inhibitors of HIV-1 protease are described. Michael addition of amino acid derivatives to vinyl ketones was utilized to derive a potent (nM) series of HIV-1 protease inhibitors.
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PMID:Design and synthesis of a novel series of HIV-1 protease inhibitors. 1053 Sep 61

We have developed synthetic approaches to novel analogues of 2-imidazolidinone scaffold 2, which was found to be an effective P1-P2 mimetic in HIV-1 protease inhibitor 4. This enabled a rapid synthesis of analogues of 4 and subsequently allowed us to evaluate and rationalize the SAR. Accordingly, trans relationship of P1 and P2 substituents in the P1-P2 mimetic, as found in a related 2-pyrrolidone-based scaffold 1, was found necessary for high potency against HIV-1 protease. Results of this study provided further rationale towards subsequent optimization of 2-pyrrolidone-based lead 3, which led us to potent and drug-like HIV-1 protease inhibitors described in a follow-on report (Bioorg. Med. Chem. Lett. 2004, 14, in press. ).
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PMID:Potent inhibitors of the HIV-1 protease incorporating cyclic urea P1-P2 scaffold. 1548 48

We have developed efficient syntheses of the HIV-1 protease inhibitor 4 and its analogues, which incorporate the pyrrolidone scaffold 2 as P1-P2 moiety. Evaluation of these analogues in the HIV-1 protease enzyme assay resulted in discovery of potent and more water soluble meta-amino- and meta-hydroxy inhibitors 17b and 19b. The SAR observed in this class of PIs could be rationalized with aid of the X-ray structure of inhibitor 28 co-crystallized with the HIV-1 protease, which suggested that the polar meta- (but not para-) benzyl substituents in P2 could side-step the hydrophobic S2 enzyme active pocket by rotating the P2 moiety around its Cbeta-Cgamma bond. Such reorientation allows to engage the unsubstituted, hydrophobic edge of benzyl moiety in P2 in the requisite P2/S2 hydrophobic interaction, and projects polar meta-substituent into the bound water. It appears that the meta-position can be chemically derivatized without potency loss of thus resulting inhibitors, as evidenced by potent 22-26. We thus identified pyrrolidone 2-based inhibitors exemplified by 17b and 19b, which uniquely accommodate both high enzyme potency and which provide a platform for fine-tuning of drug-like properties in this class of PIs by additional chemical manipulations on the meta-position.
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PMID:Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties. 1548 49

Seven highly informative accounts of drug discovery and design were delivered by members of an international panel of speakers. The evolution of a new drug treatment for schizophrenia commenced with the observation that chlorpromazine possessed "neuroleptic" activity and progressed through studies with various dopamine and serotonin antagonists to ultimately lead to the discovery of risperidone. The 20-amino-acid peptide bivalirudin was rationally derived from hirudin. The alkoxypolyaryl derivative LY-303366 emerged from a second-generation chemical program with the aim of improving the solubility and pharmacokinetic profile of cilofungin. Antiviral activity in the low nanomolar range, combined with oral bioavailability and a clean safety profile, resulted in the development of saquinavir mesylate as the first HIV proteinase inhibitor to become available as a marketed drug. The marimastat drug design program was based on knowledge of the collagenase cleavage site, and molecules incorporated features to allow them to coordinate with the active site zinc atom and side chains that allowed interaction with the enzyme subsites. Initial lead compounds in the anastrozole development program were azoles incorporated onto nonsteroidal estrogen-like scaffolds. Chance synthesis of a nitrile intermediate needed for the naphthalene analogues and further elaboration eventually led to this potent and selective aromatase inhibitor. Rosiglitazone emerged from an SAR program on ciglitazone in which the lipophilic cyclohexyl group was replaced by aromatic and polar groups.
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PMID:Case histories in drug discovery and design. 1561 42

The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.
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PMID:Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. 1577 27

As part of our efforts to identify potent HIV-1 protease inhibitors that are active against resistant viral strains, structural modification of the azacyclic urea (I) was undertaken by incorporating acyl groups as P(1)' ligands. The extensive SAR study has yielded a series of N-acyl azacyclic ureas (II), which are highly potent against both wild-type and multiple PI-resistant viral strains.
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PMID:Synthesis and activity of N-acyl azacyclic urea HIV-1 protease inhibitors with high potency against multiple drug resistant viral strains. 1620 41

Due to factors such as resistance and long-term side effects as well as dosing regimen-related adherence issues, HIV therapy is a constantly moving target. HIV-1 protease inhibitors had an immediate and dramatic impact on the outcome of HIV/AIDS when launched in late 1995, and the search for new and improved next generation molecules has been under way in many laboratories. At GlaxoSmithKline (GSK) and Vertex Pharmaceuticals, this effort focused on two key issues, patient compliance and viral resistance. Using a water-solubilizing prodrug approach, the pill-burden in delivering our protease inhibitor, amprenavir, was dramatically decreased. By eliminating the large amounts of excipients necessary for the original soft-gel formulation, fosamprenavir (Lexiva/Telzir) delivers the clinically efficacious dose of amprenavir with two compact tablets per dose, compared to eight gel capsules. Our efforts to overcome viral resistance to 1(st) generation protease inhibitors by further elaborating the SAR of the amprenavir and related scaffolds, led to successive and dramatic improvements in wild-type antiviral potencies, and ultimately to the discovery of "ultra-potent" molecules with very favorable overall resistance profiles. The selection of GW640385 (brecanvir--USAN approved only) as a clinical candidate and its progression into current phase 2 dose ranging studies represents the culmination of our effort toward next generation protease inhibitors.
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PMID:Discovery of next generation inhibitors of HIV protease. 1637 44


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