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Klon A.E.,Ansaris
Expert Opinion on Drug Metabolism and Toxicology | Year: 2010

Importance of the field: The cost of developing new drugs is estimated at ∼ $1 billion; the withdrawal of a marketed compound due to toxicity can result in serious financial loss for a pharmaceutical company. There has been a greater interest in the development of in silico tools that can identify compounds with metabolic liabilities before they are brought to market. Areas covered in this review: The two largest classes of machine learning (ML) models, which will be discussed in this review, have been developed to predict binding to the human ether-a-go-go related gene (hERG) ion channel protein and the various CYP isoforms. Being able to identify potentially toxic compounds before they are made would greatly reduce the number of compound failures and the costs associated with drug development. What the reader will gain: This review summarizes the state of modeling hERG and CYP binding towards this goal since 2003 using ML algorithms. Take home message: A wide variety of ML algorithms that are comparable in their overall performance are available. These ML methods may be applied regularly in discovery projects to flag compounds with potential metabolic liabilities. © 2010 Informa UK Ltd.

Konteatis Z.D.,Ansaris
Expert Opinion on Drug Discovery | Year: 2010

Importance of the field: In silico fragment-based drug design (FBDD) is a relatively new approach inspired by the success of the biophysical fragment-based drug discovery field. Here, we review the progress made by this approach in the last decade and showcase how it complements and expands the capabilities of biophysical FBDD and structure-based drug design to generate diverse, efficient drug candidates. Areas covered in this review: Advancements in several areas of research that have enabled the development of in silico FBDD and some applications in drug discovery projects are reviewed. What the reader will gain: The reader is introduced to various computational methods that are used for in silico FBDD, the fragment library composition for this technique, special applications used to identify binding sites on the surface of proteins and how to assess the druggability of these sites. In addition, the reader will gain insight into the proper application of this approach from examples of successful programs. Take home message: In silico FBDD captures a much larger chemical space than high-throughput screening and biophysical FBDD increasing the probability of developing more diverse, patentable and efficient molecules that can become oral drugs. The application of in silico FBDD holds great promise for historically challenging targets such as proteinprotein interactions. Future advances in force fields, scoring functions and automated methods for determining synthetic accessibility will all aid in delivering more successes with in silico FBDD. © 2010 Informa UK, Ltd.

Gardner E.R.,SAIC | Kelly M.,Ansaris | Springman E.,Ansaris | Lee K.-J.,Ansaris | And 4 more authors.
Investigational New Drugs | Year: 2012

LP-261 is a novel tubulin targeting anticancer agent that binds at the colchicine site on tubulin, inducing G2/M arrest. Screening in the NCI60 cancer cell lines resulted in a mean GI50 of approximately 100 nM. Here, we report the results of testing in multiple mouse xenograft models and angiogenesis assays, along with bioavailability studies. To determine the antiangiogenic activity of LP-261, both in vitro and ex vivo experiments were performed. Human Umbilical Vein Endothelial cells (HUVECs) were incubated with LP-261 at 50 nM to 10 μM. LP-261 was also tested in a rat aortic ring assay, from 20 nM to 10 μM. Multiple mouse xenograft studies were performed to assess in vivo antitumor activity. LP-261 was tested as a single agent in colon adenocarcinoma (SW620) and prostate cancer (LNCaP and PC3) xenografts, evaluating several different dosing schedules. LP-261 was also used in combination with bevacizumab in the SW620 xenograft model. LP-261 also exhibited high oral bioavailability and apparent lack of efflux by intestinal transporters such as ABCB1. LP-261 is a very potent inhibitor of angiogenesis, preventing microvessel outgrowth in the rat aortic ring assay and HUVEC cell proliferation at nanomolar concentrations. Complete inhibition of tumor growth was achieved in the PC3 xenograft model and shown to be schedule dependent. Excellent inhibition of tumor growth in the SW620 model was observed, comparable with paclitaxel. Combining oral, low dose LP-261 with bevacizumab led to significantly improved tumor inhibition. Oral LP-261 is very effective at inhibiting tumor growth in multiple mouse xenograft models and is well tolerated. © Springer Science+Business Media, LLC 2010.

MacHrouhi F.,Ansaris | Ouhamou N.,Ansaris | Laderoute K.,SRI International | Calaoagan J.,SRI International | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5′-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK. © 2010 Elsevier Ltd. All rights reserved.

Laderoute K.R.,SRI International | Calaoagan J.M.,SRI International | Madrid P.B.,SRI International | Klon A.E.,Ansaris | Ehrlich P.J.,Ansaris
Cancer Biology and Therapy | Year: 2010

AMPK has been termed the fuel sensor of mammalian cells because it directly responds to the depletion of the fuel molecule ATP. In previous work, we found that AMPK is strongly activated by tumor-like hypoxia and glucose deprivation, independently of the oxygen response system associated with HIF-1. We also observed high levels of AMPK activity in tumor cells in vivo, using different model tumors. These findings suggested the hypothesis that modulation of AMPK activity could have therapeutic value for the treatment of solid tumors. To investigate this hypothesis, we have been conducting a SAR study of potential small-molecule modulators of AMPK activity. here we report that the chemotherapeutic drug SU11248 (sunitinib) is at least as potent an inhibitor of AMPK as compound C, which is a commonly used experimental direct inhibitor of the enzyme. We also provide a computational model of the binding pose of SU11248 to an AMPKα subunit, which suggests a structural basis for the affinity of the drug for the ATP site of the catalytic domain. The ability of SU11248 to inhibit AMPK has potential clinical significance - there may be populations of SU11248-treated patients in which AMPK activity is inhibited in normal as well as in tumor tissue. © 2010 Landes Bioscience.

Meshkat S.,Ansaris | Klon A.E.,Ansaris | Zou J.,Ansaris | Wiseman J.S.,Ansaris | And 2 more authors.
Journal of Chemical Information and Modeling | Year: 2011

We introduce TICRA (transplant-insert-constrain-relax-assemble), a method for modeling the structure of unknown protein-ligand complexes using the X-ray crystal structures of homologous proteins and ligands with known activity. We present results from modeling the structures of protein kinase-inhibitor complexes using p38 and Lck as examples. These examples show that the TICRA method may be used prospectively to create and refine models for protein kinase-inhibitor complexes with an overall backbone rmsd of less than 0.75 Å for the kinase domain, when compared to published X-ray crystal structures. Further refinement of the models of the kinase domains of p38 and Lck in complex with their cognate ligands from the published crystal structures was able to improve the rmsd's of the model complexes to below 0.5 Å. Our results show that TICRA is a useful approach to the problem of structure-based drug design in cases where little structural information is available for the target proteins and the binding mode of active compounds is unknown. © 2011 American Chemical Society.

Liu B.,Ansaris | Lee Y.,Ansaris | Zou J.,Ansaris | Petrassi H.M.,Ansaris | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

The discovery and SAR study of a series of 4,6-diamino-1,3,5-triazin-2-ol compounds as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are reported. The lead compounds in this series showed excellent activity against wild-type and drug-resistant RT enzymes and viral strains. In addition, compounds from this series demonstrated favorable pharmacokinetic profile in rat. A preliminary modeling study was conducted to understand the binding mode of this series of compounds. © 2010 Elsevier Ltd. All rights reserved.

Reynolds C.H.,Ansaris | Holloway M.K.,Merck And Co.
ACS Medicinal Chemistry Letters | Year: 2011

Analysis of the experimental binding thermodynamics for approximately 100 protein-ligand complexes provides important insights into the factors governing ligand affinity and efficiency. The commonly accepted correlation between enthalpy and -TδS is clearly observed for this relatively diverse data set. It is also clear that affinity (i.e., δG) is not generally correlated to either enthalpy or -TδS. This is a worrisome trend since the vast majority of computational structure-based design is carried out using interaction energies for one, or at most a few, ligand poses. As such, these energies are most closely comparable to enthalpies not free energies. Closer inspection of the data shows that in a few cases the enthalpy (or -TδS) is correlated with free energy. It is tempting to speculate that this could be an important consideration as to why some targets are readily amenable to modeling and others are not. Additionally, analysis of the enthalpy and -TδS efficiencies shows that the trends observed for ligand efficiencies with respect to molecular size are primarily a consequence of enthalpic, not entropic, effects. © 2011 American Chemical Society.

Liu B.,Ansaris | Shetty R.S.,Ansaris | Moffett K.K.,Ansaris | Kelly M.J.,Ansaris
Tetrahedron Letters | Year: 2011

An efficient synthesis of 1,3,5-trisubstituted benzenes via a sequential Pd-mediated carbon-sulfur, carbon-nitrogen, and carbon-carbon bond formation reactions is reported. Selective amidation and sulfonamidation reactions are accomplished via Pd-catalyzed reactions between aryl chlorides and an acetamide or a methanesulfonamide. © 2011 Elsevier Ltd. All rights reserved.

Konteatis Z.D.,Ansaris | Klon A.E.,Ansaris | Zou J.,Ansaris | Meshkat S.,Ansaris
Methods in Enzymology | Year: 2011

Abstract In silico fragment-based drug discovery has become an integral component of the new fragment-based approach that has evolved over the past decade. Protein structure of high quality is essential in carrying out computational designs, and protein flexibility has been shown to impact prospective designs or docking experiments. Here we introduce methodology to calculate protein normal modes and protein molecular dynamics in torsion space which enable the development of multiple protein states to address the natural flexibility of proteins. We also present two fragment-based sampling methods, grand canonical Monte Carlo and systematic sampling, which are used to study proteinfragment interactions by generating fragment ensembles and we discuss the process by which these ensembles are linked to design ligands. © 2011 Elsevier Inc.

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