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1.  Insights into the Mechanism of Streptonigrin-Induced Protein Arginine Deiminase Inactivation 
Bioorganic & medicinal chemistry  2014;22(4):1362-1369.
Protein citrullination is just one of more than 200 known PTMs. This modification, catalyzed by the Protein Arginine Deiminases (PADs 1–4 and PAD6 in humans), converts the positively charged guanidinium group of an arginine residue into a neutral ureido-group. Given the strong links between dysregulated PAD activity and human disease, we initiated a program to develop PAD inhibitors as potential therapeutics for these and other diseases in which the PADs are thought to play a role. Streptonigrin which possesses both anti-tumor and anti-bacterial activity was later identified as a highly potent PAD4 inhibitor. In an effort to understand why streptonigrin is such a potent and selective PAD4 inhibitor, we explored its structure-activity relationships by examining the inhibitory effects of several analogues that mimic the A, B, C, and/or D rings of streptonigrin. We report the identification of the 7-amino-quinoline-5,8-dione core of streptonigrin as a highly potent pharmacophore that acts as a pan-PAD inhibitor.
PMCID: PMC3954981  PMID: 24440480
PADs; Streptonigrin; 7-amino-quinoline-5,8-dione; Protein arginine deiminase; Irreversible inhibitors
2.  Synthesis and Biological Evaluation of Coumarin Replacements of Novobiocin as Hsp90 Inhibitors 
Bioorganic & medicinal chemistry  2014;22(4):1441-1449.
Since Hsp90 modulates all six hallmarks of cancer simultaneously, it has become an attractive target for the development of cancer chemotherapeutics. In an effort to develop more efficacious compounds for Hsp90 inhibition, novobiocin analogues were prepared by replacing the central coumarin core with naphthalene, quinolinone, and quinoline surrogates. These modifications allowed for modification of the 2-position, which was previously unexplored. Biological evaluation of these compounds suggests a hydrophobic pocket about the 2-position of novobiocin. Anti-proliferative activities of these analogues against multiple cancer cell lines identified 2-alkoxyquinoline derivatives to exhibit improved activity.
PMCID: PMC3963410  PMID: 24461493
3.  3-Ketone-4,6-diene ceramide analogs exclusively induce apoptosis in chemo-resistant cancer cells 
Bioorganic & medicinal chemistry  2014;22(4):1412-1420.
Multidrug-resistance is a major cause of cancer chemotherapy failure in clinical treatment. Evidence shows that multidrug-resistant cancer cells are as sensitive as corresponding regular cancer cells under the exposure to anticancer ceramide analogs. In this work we designed five new ceramide analogs with different backbones, in order to test the hypothesis that extending the conjugated system in ceramide analogs would lead to an increase of their anticancer activity and selectivity towards resistant cancer cells. The analogs with the 3-ketone-4,6-diene backbone show the highest apoptosis-inducing efficacy. The most potent compound, analog 406, possesses higher pro-apoptotic activity in chemo-resistant cell lines MCF-7TN-R and NCI/ADR-RES than the corresponding chemo-sensitive cell lines MCF-7 and OVCAR-8, respectively. However, this compound shows the same potency in inhibiting the growth of another pair of chemo-sensitive and chemo-resistant cancer cells, MCF-7 and MCF-7/Dox. Mechanism investigations indicate that analog 406 can induce apoptosis in chemo-resistant cancer cells through the mitochondrial pathway. Cellular glucosylceramide synthase assay shows that analog 406 does not interrupt glucosylcer-amide synthase in chemo-resistant cancer cell NCI/ADR-RES. These findings suggest that due to certain intrinsic properties, ceramide analogs’ pro-apoptotic activity is not disrupted by the normal drug-resistance mechanisms, leading to their potential use for overcoming cancer multidrug-resistance.
PMCID: PMC3967587  PMID: 24457089
Ceramide; Glucosylceramide synthase (GCS); P-glycoprotein; Multidrug resistance; Anti-cancer drugs
4.  Synthesis of a C-phosphonate mimic of maltose-1-phosphate and inhibition studies on Mycobacterium tuberculosis GlgE 
Bioorganic & medicinal chemistry  2014;22(4):1404-1411.
The emergence of extensively drug-resistant tuberculosis (XDR-TB) necessitates the need to identify new anti-tuberculosis drug targets as well as to better understand essential biosynthetic pathways. GlgE is a Mycobacterium tuberculosis (Mtb) encoded maltosyltransferase involved in α-glucan biosynthesis. Deletion of GlgE in Mtb results in the accumulation of M1P within cells leading to rapid death of the organism. To inhibit GlgE a maltose-C-phosphonate (MCP) 13 was designed to act as an isosteric non-hydrolysable mimic of M1P. MCP 13, the only known inhibitor of Mtb GlgE, was successfully synthesized using a Wittig olefination as a key step in transforming maltose to the desired product. MCP 13 inhibited Mtb GlgE with an IC50 = 230 ± 24 μM determined using a coupled enzyme assay which measures orthophosphate release. The requirement of M1P for the assay necessitated the development of an expedited synthetic route to M1P from an intermediate used in the MCP 13 synthesis. In conclusion, we designed a substrate analogue of M1P that is the first to exhibit Mtb GlgE inhibition.
PMCID: PMC4023634  PMID: 24461562
Mycobacterium tuberculosis; GlgE; C-phosphonates; Enzyme inhibition; Maltose-1-phosphate
5.  [No title available] 
PMCID: PMC3919520  PMID: 24360826
6.  [No title available] 
PMCID: PMC3976583  PMID: 24412338
7.  Structure–activity relationships of substituted oxyoxalamides as inhibitors of the human soluble epoxide hydrolase 
Bioorganic & medicinal chemistry  2014;22(3):1163-1175.
We explored both structure–activity relationships among substituted oxyoxalamides used as the primary pharmacophore of inhibitors of the human sEH and as a secondary pharmacophore to improve water solubility of inhibitors. When the oxyoxalamide function was modified with a variety of alkyls or substituted alkyls, compound 6 with a 2-adamantyl group and a benzyl group was found to be a potent sEH inhibitor, suggesting that the substituted oxyoxalamide function is a promising primary pharmacophore for the human sEH, and compound 6 can be a novel lead structure for the development of further improved oxyoxalamide or other related derivatives. In addition, introduction of substituted oxyoxalamide to inhibitors with an amide or urea primary pharmacophore produced significant improvements in inhibition potency and water solubility. In particular, the N,N,O-trimethyloxyoxalamide group in amide or urea inhibitors (26 and 31) was most effective among those tested for both inhibition and solubility. The results indicate that substituted oxyoxalamide function incorporated into amide or urea inhibitors is a useful secondary pharmacophore, and the resulting structures will be an important basis for the development of bioavailable sEH inhibitors.
PMCID: PMC4172381  PMID: 24433964
Substituted oxyoxalamides; Human soluble epoxide hydrolase; Inhibitors
8.  Anticancer activity and SAR studies of substituted 1,4-naphthoquinones 
Bioorganic & medicinal chemistry  2013;21(15):4662-4669.
In this paper, we report the structure–activity relationship studies of substituted 1,4-naphthoquinones for its anticancer properties. 1,4-Naphthoquinone, Juglone, Menadione, Plumbagin and LLL12.1 were used as lead molecules to design PD compounds. Most of the PD compounds showed improved antiproliferative activity in comparison to the lead molecule in prostate (DU-145), breast (MDA-MB-231) and colon (HT-29) cancer cell lines. PD9, PD10, PD11, PD13, PD14 and PD15 were found to be the most potent compound with an IC50 value of 1–3 μM in all cancer cell lines. Fluorescent polarization assay was employed to study the inhibition of STAT3 dimerization by PD compounds. PD9 and PD18 were found to be potent STAT3 dimerization inhibitors.
PMCID: PMC4304211  PMID: 23791367
1, 4-Naphthoquinone; Plumbagin; Juglone; LLL12.1; Menadione; STAT3
9.  Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure–activity relationship leads to selection of candidates with desirable in vivo properties 
Bioorganic & medicinal chemistry  2012;20(14):4451-4461.
Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day.
PMCID: PMC4304654  PMID: 22717239
Alzheimer’s disease; Tauopathy; Aminothienopyridazine; Tau aggregation inhibitor; K18PL
10.  Structurally diverse low molecular weight activators of the mammalian pre-mRNA 3′ cleavage reaction 
Bioorganic & medicinal chemistry  2013;22(2):834-841.
The 3′ end formation of mammalian pre-mRNA contributes to gene expression regulation by setting the downstream boundary of the 3′ untranslated region, which in many genes carries regulatory sequences. A large number of protein cleavage factors participate in this pre-mRNA processing step, but chemical tools to manipulate this process are lacking. Guided by a hypothesis that a PPM1 family phosphatase negatively regulates the 3′ cleavage reaction, we have found a variety of new small molecule activators of the in vitro reconstituted pre-mRNA 3′ cleavage reaction. New activators include a cyclic peptide PPM1D inhibitor, a dipeptide with modifications common to histone tails, abscisic acid and an improved L-arginine β-naphthylamide analog. The minimal concentration required for in vitro cleavage has been improved from 200 μM to the 200 nM-100 μM range. These compounds provide unexpected leads in the search for small molecule tools able to affect pre-mRNA 3′ end formation.
PMCID: PMC4018835  PMID: 24373842
11.  4,4′-unsymmetrically substituted 3,3′-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors 
Bioorganic & medicinal chemistry  2013;22(2):917-926.
A series of unsymmetrically substituted biphenyl compounds was designed as alpha helical proteomimetics with the aim of inhibiting the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were synthesized in good overall yields in seven steps starting from 2-bromoanisole. The final products were evaluated using cotransfection reporter gene assays and mammalian two-hybrid competitive inhibition assays to demonstrate their effectiveness as competitive binding inhibitors. The results from this study indicate that these proteomimetics possess the ability to inhibit coactivator-receptor interactions, but via a mixed mode of inhibition.
PMCID: PMC4243926  PMID: 24360824
Proteomimetic; Co-activator binding inhibition; Nuclear receptor
12.  Comparative Molecular Field Analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β2-adrenergic receptor 
Bioorganic & medicinal chemistry  2013;22(1):234-246.
The β2-adrenergic receptor (β2-AR) agonist [3H]-(R,R′)-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4′-methoxyfenoterol analogs in which the length of the alkyl substituent at α′ position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [3H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC50 values, were determined in HEK293 cells expressing the β2-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α′ position. The results also indicate that the Ki values obtained using [3H]-(R,R′)-methoxyfenoterol as the marker ligand modeled the EC50 values obtained from cAMP stimulation better than the data obtained using [3H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β2-AR conformation probed by [3H]-(R,R′)-4′-methoxyfenoterol. The CoMFA model of the agonist-stabilized β2-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β2-AR is governed to a greater extend by steric effects than binding to the [3H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role.
PMCID: PMC3908673  PMID: 24326276
β2-adrenoceptor selective agonist; β2-adrenoceptor conformations; agonist-stabilized conformations; antagonist-stabilized conformations; [3H]-(R,R′)-4′-methoxyfenoterol
Bioorganic & medicinal chemistry  2013;22(1):538-549.
Butyrylcholinesterase (BChE) has been an important protein used for development of anti-cocaine medication. Through computational design, BChE mutants with ~2000-fold improved catalytic efficiency against cocaine have been discovered in our lab. To study drug-enzyme interaction it is important to build mathematical model to predict molecular inhibitory activity against BChE. This report presents a neural network (NN) QSAR study, compared with multi-linear regression (MLR) and molecular docking, on a set of 93 small molecules that act as inhibitors of BChE by use of the inhibitory activities (pIC50 values) of the molecules as target values. The statistical results for the linear model built from docking generated energy descriptors were: r2 = 0.67, rmsd = 0.87, q2 = 0.65 and loormsd = 0.90; The statistical results for the ligand-based MLR model were: r2 = 0.89, rmsd = 0.51, q2 = 0.85 and loormsd = 0.58; the statistical results for the ligand-based NN model were the best: r2 = 0.95, rmsd = 0.33, q2 = 0.90 and loormsd = 0.48, demonstrating that the NN is powerful in analysis of a set of complicated data. As BChE is also an established drug target to develop new treatment for Alzheimer’s disease (AD). The developped QSAR models provide tools for rationalizing identification of potential BChE inhibitors or selection of compounds for synthesis in the discovery of novel effective inhibitors of BChE in the future.
PMCID: PMC3919557  PMID: 24290065
14.  Isolation of antiplasmodial anthraquinones from Kniphofia ensifolia, and synthesis and structure-activity relationships of related compounds 
Bioorganic & medicinal chemistry  2013;22(1):269-276.
Bioassay-guided separation of the South African plant Kniphofia ensifolia for antiplasmodial activity led to the isolation of two new anthraquinones, named kniphofiones A and B (3, 4), together with three known bioactive anthraquinone monomers (1, 2 and 5), and four known bisanthraquinones (6–9). The structures of the two new compounds were elucidated based on analyses of their 1D and 2D NMR spectra and mass spectrometric data. The dimeric compounds 6 and 7 displayed the strongest antiplasmodial activity among all the isolated compounds, with IC50 values of 0.4 ± 0.1 and 0.2 ± 0.1 μM, respectively. The two new compounds displayed modest activities, with IC50 values of 26 ± 4 and 9 ± 1 μM, respectively. Due to the synthetic accessibility of the new compounds and the increased activity shown by the dimeric compounds, a structure-activity relationship study was conducted. As a result, one analogue of kniphofione B (4), the caffeic acid derivative of aloe-emodin, was found to have the highest activity among all the aloe-emodin derivatives, with an IC50 value of 1.3 ± 0.2 μM.
PMCID: PMC3919637  PMID: 24326280
Anthraquinone; Antiplasmodial acitivity; Kniphofia ensifolia; Structure-activity relationship
15.  Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors☆ 
Bioorganic & medicinal chemistry  2013;22(1):126-134.
Fluorinated isoflavanones and bifunctionalized isoflavanones were synthesized through a one-step gold(I)-catalyzed annulation reaction. These compounds were evaluated for their in vitro inhibitory activities against aromatase in a fluorescence-based enzymatic assay. Selected compounds were tested for their anti-proliferative effects on human breast cancer cell line MCF-7. Compounds 6-methoxy-3-(pyridin-3-yl)chroman-4-one (3c) and 6-fluoro-3-(pyridin-3-yl)chroman-4-one (3e) were identified as the most potent aromatase inhibitors with IC50 values of 2.5 μM and 0.8 μM. Therefore, these compounds have great potential for the development of pharmaceutical agents against breast cancer.
PMCID: PMC3933948  PMID: 24345481
Breast cancer; Estrogen; Aromatase inhibitors; Fluorine; Isoflavanones; Functional groups
16.  Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents 
Bioorganic & medicinal chemistry  2013;22(1):116-125.
A series of pateamine A (1) derivatives were synthesized for structure/activity relationship (SAR) studies and a selection of previous generation analogs were re-evaluated based on current information regarding the mechanism of action of these translation inhibitors. Structural modifications in the new generation of derivatives focused on alternations to the C19-C22 Z, E-diene and the trienyl side chain of the previously described simplified, des-methyl, des-amino pateamine A (DMDAPatA, 2). Derivatives were tested for anti-proliferative activity in cell culture and for inhibition of mammalian cap-dependent translation in vitro. Activity was highly dependent on the rigidity and conformation of the macrolide and the functionality of the side chain. The only well tolerated substitutions were replacement of the N,N-dimethyl amino group found on the side chain of 2 with other tertiary amine groups. SAR reported here suggests that this site may be modified in future studies to improve serum stability, cell-type specificity, and/or specificity towards rapidly proliferating cells.
PMCID: PMC3958936  PMID: 24359706
Pateamine A; DMDAPatA; Stille coupling; Translation initiation; eIF4A
17.  Identification of novel drug scaffolds for inhibition of SARS-CoV 3-Chymotrypsin-like protease using virtual and high-throughput screenings 
Bioorganic & medicinal chemistry  2013;22(1):167-177.
We have used a combination of virtual screening (VS) and high-throughput screening (HTS) techniques to identify novel, non-peptidic small molecule inhibitors against human SARS-CoV 3CLpro. A structure-based VS approach integrating docking and pharmacophore based methods was employed to computationally screen 621,000 compounds from the ZINC library. The screening protocol was validated using known 3CLpro inhibitors and was optimized for speed, improved selectivity, and for accommodating receptor flexibility. Subsequently, a fluorescence-based enzymatic HTS assay was developed and optimized to experimentally screen approximately 41,000 compounds from four structurally diverse libraries chosen mainly based on the VS results. False positives from initial HTS hits were eliminated by a secondary orthogonal binding analysis using surface plasmon resonance (SPR). The campaign identified a reversible small molecule inhibitor exhibiting mixed-type inhibition with a Ki value of 11.1 μM. Together, these results validate our protocols as suitable approaches to screen virtual and chemical libraries, and the newly identified compound reported in our study represents a promising structural scaffold to pursue for further SARS-CoV 3CLpro inhibitor development.
PMCID: PMC3971864  PMID: 24332657
SARS 3CLpro; Virtual screening; Docking; Pharmacophore modeling; High-throughput screening; Surface plasmon resonance
18.  Discovery of Novel Antitumor Dibenzocyclooctatetraene Derivatives and Related Biphenyls as Potent Inhibitors of NF-κB Signaling Pathway 
Bioorganic & medicinal chemistry  2013;22(1):325-333.
Several dibenzocyclooctatetraene derivatives (5-7) and related biphenyls (8-11) were designed, synthesized, and evaluated for inhibition of cancer cell growth and the NF-κB signaling pathway. Compound 5a, a dibenzocyclooctatetraene succinimide, was discovered as a potent inhibitor of the NF-κB signaling pathway with significant antitumor activity against several human tumor cell lines (GI50 1.38–1.45 μM) and was more potent than paclitaxel against the drug-resistant KBvin cell line. Compound 5a also inhibited LPS-induced NF-κB activation in RAW264.7 cells with an IC50 value of 0.52 μM, prevented IκB-α degradation and p65 nuclear translocation, and suppressed LPS-induced NO production in a dose-dependent manner. The antitumor data in cellular assays indicated that relative positions and types of substituents on the dibenzocyclooctatetraene or acyclic biphenyl as well as torsional angles between the two phenyls are of primary importance to antitumor activity.
PMCID: PMC3899348  PMID: 24315191
dibenzocyclooctatetraene derivatives; unsymmetrical biphenyls; anticancer agents; NF-κB inhibitor
19.  New Insights into Molecular Recognition of 1,1-Bisphosphonic Acids by Farnesyl Diphosphate Synthase 
Bioorganic & medicinal chemistry  2013;22(1):398-405.
As part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bishosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED50 value of 4.7 μM against tachyzoites of T. gondii and an IC50 of 0.051 μM against TgFPPS.
PMCID: PMC3902031  PMID: 24300918
20.  Design, Synthesis and Cytotoxic Activity of Novel Sulfonylurea Derivatives of Podophyllotoxin 
Bioorganic & medicinal chemistry  2013;22(1):204-210.
Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC50: 1.41–1.76 μM) and 14e (IC50: 1.72–2.01 μM) showed superior cytotoxic activity compared with etoposide (IC50: 2.03– >20μM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure-activity relationship (SAR) correlations indicated that the 4′-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin’s 4β position can significantly improve cytotoxic activity.
PMCID: PMC3902999  PMID: 24332656
podophyllotoxin; sulfonylurea; synthesis; cytotoxic activity
21.  Flexible and biomimetic analogs of triple uptake inhibitor 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol : Synthesis, biological characterization, and development of a pharmacophore model 
Bioorganic & medicinal chemistry  2013;22(1):311-324.
In this study we have generated a pharmacophore model of triple uptake inhibitor compounds based on novel asymmetric pyran derivatives and the newly developed asymmetric furan derivatives. The model revealed features important for inhibitors to exhibit a balanced activity against dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). In particular, a ‘folded’ conformation was found common to the active pyran compounds in the training set and was crucial to triple uptake inhibitory activity. Furthermore, the distances between the benzhydryl moiety and the N-benzyl group as well as the orientation of the secondary nitrogen were also important for TUI activity. We have validated our findings by synthesizing and testing novel asymmetric pyran analogs. The present work has also resulted in the discovery of a new series of asymmetric tetrahydrofuran derivatives as novel TUIs. Lead compounds 41 and 42 exhibited moderate TUI activity. Interestingly, the highest TUI activity by lead tetrahydrofuran compounds e.g. 41 and 42, was exhibited in a stereochemical preference similar to pyran TUI e.g. D-161.
PMCID: PMC3913050  PMID: 24315194
22.  Strategies for Lead Discovery: Application of Footprint Similarity Targeting HIVgp41 
Bioorganic & medicinal chemistry  2013;22(1):651-661.
A highly-conserved binding pocket on HIVgp41 is an important target for development of anti-viral inhibitors. Holden et al. (Bioorg. Med. Chem. Lett. 2012) recently reported 7 experimentally-verified leads identified through a computational screen to the gp41 pocket in conjunction with a new DOCK scoring method (termed FPS scoring) developed in our laboratory. The method employs molecular footprints based on per-residue van der Waals interactions, electrostatic interactions, or the sum. In this work, we critically examine the gp41 screening results, prioritized using different scoring methods, in terms of two main criteria: (1) ligand pose properties which include footprint and energy score decompositions, MW, number of rotatable bonds, ligand efficiency, formal charge, and volume overlap, and (2) ligand pose stability which includes footprint stability (changes in footprint overlap) and rmsd stability (changes in geometry). Relative to standard DOCK scoring, pose property analyses demonstrate how FPS scoring can be used to identify ligands that mimic a known reference (derived here from the native gp41 substrate), while pose stability analyses demonstrate how FPS scoring can be used to enrich for compounds with greater overall stability during molecular dynamics (MD) simulations. Compellingly, of the 115 compounds tested experimentally, the 7 active compounds, as a group, more closely mimic the footprints made by the reference and show greater MD stability compared to the inactive group. Extensive studies using 116 protein-ligand complexes as controls reveal that ligands in their crystallographic binding pose also maintain higher FPS scores and smaller rmsds than do accompanying decoys, confirming that native poses are indeed “stable” under the same conditions and that monitoring FPS variability during compound prioritization is likely to be beneficial. Overall, the results suggest the new scoring method will complement current virtual screening approaches for both the identification (FPS-ranking) and prioritization (FPS-stability) of target-compatible molecules in a quantitative and logical way.
PMCID: PMC3913180  PMID: 24315195
HIV; gp41; Protein-protein interactions; Docking; Virtual screening; DOCK; Footprint similarity; Scoring functions; Molecular dynamics
23.  Synthesis of 3-(3-Aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazines That Have Antibacterial Activity and Also Inhibit Inorganic Pyrophosphatase 
Bioorganic & medicinal chemistry  2013;22(1):406-418.
Inorganic pyrophosphatases are potential targets for the development of novel antibacterial agents. A pyrophosphatase-coupled high-throughput screening assay intended to detect o-succinyl benzoic acid coenzyme A (OSB CoA) inhibitors led to the unexpected discovery of a new series of novel inorganic pyrophosphatase inhibitors. Lead optimization studies resulted in a series of 3-(3-aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazine derivatives that were prepared by an efficient synthetic pathway. One of the tetracyclic triazine analogues 22h displayed promising antibiotic activity against a wide variety of drug-resistant Staphylococcus aureus strains, as well as activity vs. Mycobacterium tuberculosis and Bacillus anthracis, at a concentration that was not cytotoxic to mammalian cells.
PMCID: PMC3914758  PMID: 24315189
Inorganic pyrophosphatase; inhibitors; antibacterial agents; 3-(3-aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazine
24.  Fragment based discovery of Arginine isosteres through REPLACE: towards non-ATP competitive CDK inhibitors 
Bioorganic & medicinal chemistry  2013;22(1):616-622.
In order to develop non-ATP competitive CDK2/cyclin A inhibitors, the REPLACE strategy has been applied to generate fragment alternatives for the N-terminal tetrapeptide of the cyclin binding motif (HAKRRLIF) involved in substrate recruitment prior to phosphotransfer. The docking approach used for the prediction of small molecule mimics for peptide determinants was validated through reproduction of experimental binding modes of known inhibitors and provides useful information for evaluating binding to protein-protein interaction sites. Further to this, potential arginine isosteres predicted using the validated LigandFit docking method were ligated to the truncated C-terminal peptide, RLIF using solid phase synthesis and evaluated in a competitive binding assay. After testing, identified fragments were shown to represent not only appropriate mimics for a critical arginine residue but also to interact effectively with a minor hydrophobic pocket present in the binding groove. Further evaluation of binding modes was undertaken to optimize the potency of these compounds. Through further application of the REPLACE strategy in this study, peptide-small molecule hybrid CDK2 inhibitors were identified that are more drug-like and suitable for further optimization as anti-tumor therapeutics.
PMCID: PMC3917480  PMID: 24286762
25.  Small Molecule Inhibitors of Anthrax Lethal Factor Toxin 
Bioorganic & medicinal chemistry  2013;22(1):419-434.
This manuscript describes the preparation of new small molecule inhibitors of Bacillus anthracis lethal factor. Our starting point was the symmetrical, bis-quinolinyl compound 1 (NSC 12155). Optimization of one half of this molecule led to new LF inhibitors that were desymmetrized to afford more drug-like compounds.
PMCID: PMC3925373  PMID: 24290062
Bacillus anthracis; anthrax; lethal factor; botulinum neurotoxin A; light chain; zinc metalloprotease; matrix metalloprotease; quinoline; hybrid compound; desymmetrized

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