-
Lan Mu,
Joacy Aguiar,
Ali Ardati,
Bin Cao,
Charles J Gardner,
Tim Gillespy,
Keith Harris,
Sungtaek Lim,
Robert Marcus,
Isabelle Morize,
Ashfaq Parkar,
David Stefany,
Yi Li, Roy J Vaz,
Dragan A Cirovic
[show abstract]
[hide abstract]
ABSTRACT: A Comparative Molecular Similarity Indices Analysis (CoMSIA) was performed for 2,6-substituted-4-monosubstituted aminopyrimidine antagonists of prostaglandin D(2) receptor (DP). Both two-component (Q(2) = 0.63, R(2) = 0.82, SEE = 0.47 pIC(50)) and three-component (Q(2) = 0.70, R(2) = 0.91, SEE = 0.36 pIC(50)) CoMSIA models were established. Two hydrogen-bond acceptors with spatial separation of about 8Å are shown as optimal for binding. A large hydrophobic center that separates the two acceptors confers to the potency of the 2,6-substituted-4-monosubstituted aminopyrimidine. The models were used to predict IC(50) values for compounds which had functional groups different from those in the training set.
Bioorganic & medicinal chemistry letters 01/2011; 21(1):66-75. · 2.65 Impact Factor
-
Guyan Liang,
Yong Mi Choi-Sledeski,
Gregory Poli,
Xin Chen,
Patrick Shum,
Anne Minnich,
Qingping Wang,
Joseph Tsay,
Keith Sides,
Jennifer Cairns,
Gregory Stoklosa,
Thaddeus Nieduzak,
Zhicheng Zhao,
Jie Wang, Roy J Vaz
[show abstract]
[hide abstract]
ABSTRACT: A novel β-tryptase inhibitor with a basic benzylamine P1 group, a piperidine-amide linker, and a substituted indole P4 group was discovered. A substitution at 4-indole position was introduced to constrain the conformational flexibility of the inhibitor to the bioactive conformation exhibited by X-ray structures so that entropic penalty was decreased. More importantly, this constrained conformation limited the accessibility of this molecule to anti-targets, especially SSAO, so that an enhanced metabolic profile was achieved.
Bioorganic & medicinal chemistry letters 11/2010; 20(22):6721-4. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic receptors in living organisms and is responsible for interacting with several drugs and environmental toxins, most notably tetrachlorodibenzodioxin (TCDD). Binding of diverse agonists to AHR initiates an extensive set of downstream gene expression responses and thus identifies AHR among a key set of proteins responsible for mediating interactions between living organisms and foreign molecules. While extensive biochemical investigations on the interaction of AHR with ligands have been carried out, studies comparing the abilities of specific computational algorithms in explaining the potency of known AHR ligands are lacking. In this study we use molecular dynamics simulations to identify a physically realistic conformation of the AHR that is relevant to ligand binding. We then use two sets of existing data on known AHR ligands to evaluate the performance of several docking and scoring protocols in rationalizing the potencies of these ligands. The results identify an optimum set of protocols that could prove useful in future AHR ligand discovery and design as a target or anti-target. Exploration of the details of these protocols sheds light on factors operating in modeling AHR ligand binding.
Bioorganic & medicinal chemistry letters 09/2010; 20(22):6616-9. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The site of metabolism (SOM) predictions by CYP 3A4 are extremely important during the drug discovery process especially during the lead discovery or library design phases. With the ability to rapidly characterize metabolites from these enzymes, the challenges facing in silico contribution change during the drug optimization phase. Some of the challenges are addressed in this article. Some aspects of the SOM prediction software and methodology are discussed in this opinion article and examples of software utility in overcoming metabolic instability in drug optimization are shown.
SOM prediction by various approaches is discussed. Two ways of overcoming metabolic instability, blocking the metabolic softspots and rational modification of the instable molecule to avoid interaction with the CYP pocket, are discussed. The contribution plot in MetaSite and its use are discussed.
The reader will gain an understanding of possible approaches to either blocking the metabolic softspot or rationally modifying the molecule using MetaSite software or docking approaches. Blocking metabolism using fluorination has risks especially introducing multifluorinated benzene rings in the molecule. Take home message: During the lead optimization phase of drug discovery, when metabolic instability is an issue in a series, in silico approaches can be used to modify the molecule in order to decrease clearance due to metabolism, even that due to CYP3A4.
Expert Opinion on Drug Metabolism & Toxicology 07/2010; 6(7):851-61. · 3.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In the course of a fragment screening campaign by in silico docking followed by X-ray crystallography, a novel binding site for migration inhibitory factor (MIF) inhibitors was demonstrated. The site is formed by rotation of the side-chain of Tyr-36 to reveal a surface binding site in MIF that is hydrophobic and surrounded by aromatic side-chain residues. The crystal structures of two small inhibitors that bind to this site and of a quinolinone inhibitor, that spans the canonical deep pocket near Pro-1 and the new surface binding site, have been solved. These results suggest new opportunities for structure-based design of MIF inhibitors.
Bioorganic & medicinal chemistry letters 02/2010; 20(6):1821-4. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Amino-benzoic acid derivatives 1-4 were found to be inhibitors for DHODH by virtual screening, biochemical, and X-ray crystallographic studies. X-ray structures showed that 1 and 2 bind to DHODH as predicted by virtual screening, but 3 and 4 were found to be structurally different from the corresponding compounds initially identified by virtual screening.
Bioorganic & medicinal chemistry letters 01/2010; 20(6):1981-4. · 2.65 Impact Factor
-
Larry R McLean,
Ying Zhang,
Hua Li,
Ziyu Li,
Ulrike Lukasczyk,
Yong-Mi Choi,
Zuoning Han,
Joy Prisco,
Jeremy Fordham,
Joseph T Tsay,
Stephan Reiling, Roy J Vaz,
Yi Li
[show abstract]
[hide abstract]
ABSTRACT: Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identified by virtual screening were actually covalent inhibitors of the MIF tautomerase. Adducts were formed by N-alkylation of the Pro-1 at the catalytic site with a loss of an amino group of the inhibitor.
Bioorganic & medicinal chemistry letters 12/2009; 19(23):6717-20. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The reaction pathways of deprotonation versus nucleophilic substitution involving mPGES-2 enzyme catalysis were investigated by ab initio molecular orbital theory calculations for the reaction of methylthiolate with the endoperoxide core of PGH(2) and by the combined quantum mechanical molecular mechanical methods. The calculations showed that deprotonation mechanism is energetically more favorable than the nucleophilic substitution pathway.
Bioorganic & medicinal chemistry letters 10/2009; 20(1):338-40. · 2.65 Impact Factor
-
Tudor I Oprea,
Cristian G Bologa,
Scott Boyer,
Ramona F Curpan,
Robert C Glen,
Andrew L Hopkins,
Christopher A Lipinski,
Garland R Marshall,
Yvonne C Martin,
Liliana Ostopovici-Halip,
Gilbert Rishton,
Oleg Ursu, Roy J Vaz,
Chris Waller,
Herbert Waldmann,
Larry A Sklar
[show abstract]
[hide abstract]
ABSTRACT: Between 2004 and 2008, the US National Institutes of Health Molecular Libraries and Imaging initiative pilot phase funded 10 high-throughput screening centers, resulting in the deposition of 691 assays into PubChem and the nomination of 64 chemical probes. We crowdsourced the Molecular Libraries and Imaging initiative output to 11 experts, who expressed medium or high levels of confidence in 48 of these 64 probes.
Nature Chemical Biology 08/2009; 5(7):441-7. · 14.69 Impact Factor
-
06/2006: pages 428 - 443; , ISBN: 9783527608140
-
05/2006: pages 197 - 218; , ISBN: 9783527607679
-
Ashvinikumar V Gavai, Roy J Vaz,
Amarendra B Mikkilineni,
Jacques Y Roberge,
Yalei Liu,
R Michael Lawrence,
James R Corte,
Wu Yang,
Mark Bednarz,
John K Dickson,
Zhengping Ma,
Ramakrishna Seethala,
Jean H M Feyen
[show abstract]
[hide abstract]
ABSTRACT: A 3D quantitative structure-activity relationship study for inhibition of calcium-sensing receptor in the aryloxypropanolamine series predicted that these molecules adopt a U-shaped conformation with pi-stacking between the two aromatic rings. This hypothesis led to the discovery of novel 1-arylmethyl pyrrolidin-2-yl ethanol amines capable of antagonizing the calcium-sensing receptor with potency comparable to that of NPS-2143.
Bioorganic & Medicinal Chemistry Letters 01/2006; 15(24):5478-82. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A comparative molecular similarity index analysis (CoMSiA) has been performed for cytochrome P450 2D6 inhibition on a series of aryloxypropanolamines to determine the factors contributing to this activity. The model is in agreement with a CYP2D6 homology model constructed on the basis of the mammalian CYP2C5 crystal structure. The energy minimized conformations were generated using the systematic search methodology in Sybyl 6.7. The model not only elucidated the relationship between structure and biological activity but, more importantly, provided useful strategies to modulate CYP2D6 affinity in the aryloxypropanolamine series.
Bioorganic & Medicinal Chemistry Letters 10/2005; 15(17):3816-20. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We report here a general method for the prediction of hERG potassium channel blockers using computational models generated from correlation analyses of a large dataset and pharmacophore-based GRIND descriptors. These 3D-QSAR models are compared favorably with other traditional and chemometric based HQSAR methods.
Bioorganic & Medicinal Chemistry Letters 09/2005; 15(15):3637-42. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Trying to understand the complex interactions that substrates and inhibitors have with the efflux transporter P-glycoprotein has been the subject of various publications. In this work, we have confined our study to substrates by picking a diverse set of 129 compounds based on the efflux ratios from Caco-2 permeability measurements. These compounds were then evaluated for P-glycoprotein inhibition using a calcein-AM assay. The subsequent data was used in a 3D-QSAR analysis using GRIND pharmacophore-based and physicochemical descriptors. Pharmacophore-based descriptors produced a much more robust model than the one obtained from physicochemical-based descriptors. This supports the process proposed by Seelig and co-workers previously published whereby the substrate enters the membrane as the first step and is then recognized by P-glycoprotein in a second step. The strong correlation, highlighted by PLS statistical analysis, between pharmacophoric descriptors and inhibition values suggests that substrate interaction, with perhaps the mouth of the protein or another binding site, plays a key role in the efflux process, yielding a model in which diffusion across the membrane is less important than substrate-protein interaction. One pharmacophore emerged from the analysis of the model. We pose that the recognition elements, at least determined by the molecules used in this study, are two hydrophobic groups 16.5 A apart and two hydrogen-bond-acceptor groups 11.5 A apart and that the dimensions of the molecule also plays a role in its recognition as a substrate.
Journal of Medicinal Chemistry 05/2005; 48(8):2927-35. · 5.25 Impact Factor
-
Progress in Medicinal Chemistry 02/2005; 43:1-18.
-
Roy J Vaz,
Zhongli Gao,
James Pribish,
Xin Chen,
Julian Levell,
Larry Davis,
Eva Albert,
Maurice Brollo,
Antonio Ugolini,
Dona M Cramer, [......],
Keith Sides,
Feng Liu,
Jennifer Kwong,
Jiesheng Kang,
Sam Rebello,
Michael Elliot,
Hengkeang Lim,
Vinolia Chellaraj,
Robert W Singleton,
Yi Li
[show abstract]
[hide abstract]
ABSTRACT: We exploit the concept of using hydrogen bonds to link multiple ligands for maintaining simultaneous interactions with polyvalent binding sites. This approach is demonstrated by the syntheses and evaluation of pseudo-bivalent ligands as potent inhibitors of human beta-tryptase.
Bioorganic & Medicinal Chemistry Letters 01/2005; 14(24):6053-6. · 2.55 Impact Factor
-
Robert A Pearlstein, Roy J Vaz,
Jiesheng Kang,
Xiao-Liang Chen,
Maria Preobrazhenskaya,
Andrey E Shchekotikhin,
Alexander M Korolev,
Ludmila N Lysenkova,
Olga V Miroshnikova,
James Hendrix,
David Rampe
[show abstract]
[hide abstract]
ABSTRACT: A data set consisting of twenty-two sertindole analogues and ten structurally diverse inhibitors, spanning a wide range in potency, was analyzed using CoMSiA. A homology model of HERG was constructed from the crystal structure of the open MthK potassium channel. A complementary relationship between our CoMSiA and homology models is apparent when the long inhibitor axis is oriented parallel to the longitudinal axis of the pore, with the tail region pointed toward the selectivity filter. The key elements of the pharmacophore, the CoMSiA and the homology model are: (1) The hydrophobic feature optimally consists of an aromatic group that is capable of engaging in pi-stacking with a Phe656 side chain. Optionally, a second aromatic or hydrophobic group present in some inhibitors may contact an additional Phe656 side chain. (2) The basic nitrogen appears to undergo a pi-cation interaction with Tyr652. (3) The pore diameter (12A+), and depth of the selectivity loop relative to the intracellular opening, act as constraints on the conformation-dependent inhibitor dimensions.
Bioorganic & Medicinal Chemistry Letters 06/2003; 13(10):1829-35. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 20-fluoro-17(20)-pregnenolone derivatives were designed as enol mimics of pregnenolone. All of the targeted, novel fluoroolefins were potent inhibitors of C17(20) lyase.
Bioorganic & Medicinal Chemistry 05/2002; 10(4):929-34. · 2.92 Impact Factor
-
Roy J. Vaz,
Zhongli Gao,
James Pribish,
Xin Chen,
Julian Levell,
Larry Davis,
Eva Albert,
Maurice Brollo,
Antonio Ugolini,
Dona M. Cramer, [......],
Keith Sides,
Feng Liu,
Jennifer Kwong,
Jiesheng Kang,
Sam Rebello,
Michael Elliot,
HengKeang Lim,
Vinolia Chellaraj,
Robert W. Singleton,
Yi Li
Bioorganic & Medicinal Chemistry Letters. 14(24):6053-6056.
