Browsing by Author "Akten, Ebru Demet"

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Citation Count: 2
Altered Dynamics of S. aureus Phosphofructokinase via Bond Restraints at Two Distinct Allosteric Binding Sites
(Academic Press Ltd- Elsevier Science Ltd, 2022) Celebi, Metehan; Akten, Ebru Demet
The effect of perturbation at the allosteric site was investigated through several replicas of molecular dynamics (MD) simulations conducted on bacterial phosphofructokinase (SaPFK). In our previous work, an alternative binding site was estimated to be allosteric in addition to the experimentally reported one. To highlight the effect of both allosteric sites on receptor's dynamics, MD runs were carried out on apo forms with and without perturbation. Perturbation was achieved via incorporating multiple bond restraints for residue pairs located at the allosteric site. Restraints applied to the predicted site caused one dimer to stiffen, whereas an increase in mobility was detected in the same dimer when the experimentally resolved site was restrained. Fluctuations in C-alpha-C-alpha distances which is used to disclose residues with high potential of communication indicated a marked increase in signal transmission within each dimer as the receptor switched to a restrained state. Cross-correlation of positional fluctuations indicated an overall decrease in the magnitude of both positive and negative correlations when restraints were employed on the predicted allosteric site whereas an exact opposite effect was observed for the reported site. Finally, mutual correspondence between positional fluctuations noticeably increased with restraints on predicted allosteric site, whereas an opposite effect was observed for restraints applied on experimentally reported one. In view of these findings, it is clear that the perturbation of either one of two allosteric sites effected the dynamics of the receptor with a distinct and contrasting character. (c) 2022 Elsevier Ltd. All rights reserved.
Citation Count: 1
Assessing protein-ligand binding modes with computational tools: the case of PDE4B
(Springer, 2017) Çifii, Gülşah; Aviyente, Viktorya; Akten, Ebru Demet; Monard, Gerald
In a first step in the discovery of novel potent inhibitor structures for the PDE4B family with limited side effects we present a protocol to rank newly designed molecules through the estimation of their IC values. Our protocol is based on reproducing the linear relationship between the logarithm of experimental IC values [(IC)] and their calculated binding free energies (). From 13 known PDE4B inhibitors we show here that (1) binding free energies obtained after a docking process by AutoDock are not accurate enough to reproduce this linear relationship
Citation Count: 12
Blind Dockings of Benzothiazoles to Multiple Receptor Conformations of Triosephosphate Isomerase from Trypanosoma cruzi and Human
(Wiley-VCH Verlag GmbH, 2011) Kurkcuoglu, Zeynep; Ural, Gulgun; Akten, Ebru Demet; Doruker, Pemra
We aim to uncover the binding modes of benzothiazoles which have been reported as specific inhibitors of triosephosphate isomerase from the parasite Trypanosoma cruzi (TcTIM) by performing blind dockings on both TcTIM and human TIM (hTIM). Detailed analysis of binding sites and specific interactions are carried out based on ensemble dockings to multiple receptor conformers obtained from molecular dynamics simulations. In TcTIM dimer dockings the inhibitors preferentially bind to the tunnel-shaped cavity formed at the interface of the subunits whereas non-inhibitors mostly choose other sites. In contrast TcTIM monomer binding interface and hTIM dimer interface do not present a specific binding site for the inhibitors. These findings point to the importance of the tunnel and of the dimeric form for inhibition of TcTIM. Specific interactions of the inhibitors and their sulfonate-free derivatives with the receptor residues indicate the significance of sulfonate group for binding affinity and positioning on the TcTIM dimer interface. One of the inhibitors also binds to the active site which may explain its relatively higher inhibition effect on hTIM.
Citation Count: 0
Classification Of Distinct Conformers Of Beta < 2-Adrenergic Receptor (Beta 2-AR) Based On Binding Affinity Of Ligands Through Docking Studies
(Amer Chemical Soc, 2016) Akten, Ebru Demet; Dilcan, Gonca
B2AR reseptörü, akciğerlerin rahatlamasında ve kardiyovasküler fizyolojide rol oynamasıyla önemli bir ilaç hedefidir. Bu çalışmada, çeşitli B2AR konformasyonlarını aktif veya inaktif olarak sınıflandırmak amacıyla, aktivitesi bilinen ligantlar seçilerek onların bağlanma şekillerine göre bir sınıflandırma stratejisi oluşturulmuştur. Önceki bir çalışmada gerçekleştirilen, reseptörün inaktif halinin 2.8 μs'lik MD simülasyonunda, ligandın bağlanma bölgesinin farklı konformasyonları elde edilmiştir. Snapshotlar derlenerek bağlanma bölgesindeki beş anahtar rezidünün RMSD değerlerine göre gruplandırılmıştır. Toplamda 13 farklı konformasyon elde edilmiş ve 5 agonist, 4 ters agonist ve 4 antagonist molekülü her bir konformasyona ayrı ayrı ve 7 farklı skor fonksiyonu kullanılarak dock edilmiştir. En iyi yerleşen konformasyonlar bağlanma bölgesindeki anahtar rezidülerle olan yakınlığına göre seçilmiş ve hesaplanmıştır. Anahtar bölgeye yaklaşamayanlar elenmiş, kalanlar ise skor değerlerine göre sıralanmıştır. Bu sınıflandırma, kritik değerlendirme yapabilmek için MD konformasyonlarından önce aktivitesi bilinen aktif/inaktif kristal yapılara uygulanmıştır. Her skor fonksiyonu tarafından seçilen ve ilk 5'te bulunan MD konformasyonları aktif ve inaktif olarak sınıflandırılmıştır. Son olarak, MD konformasyonlarının ayırt ediciliğini analiz edebilmek için, seçilen bu konformasyonlar ile küçük bir dataset kullanılarak sanal tarama yapılmıştır. MD konformasyonlarının inaktif kristal yapıya göre antagonist/ters agonistler için daha seçici olduğu gözlemlenmiştir. Reseptörün alternatif konformasyonlarını üretmek ve onları sınıflandırmak, genellikle tek bir snaphot X-ray örneği ile sınırlandırılmış ilaç tasarımı çalışmalarında önemli rol oynamaktadır.
Classification of distinct conformers of beta-2 adrenergic receptor based on binding affinity of ligands through docking studies
(Kadir Has Üniversitesi, 2017) Dilcan, Gonca; Akten, Ebru Demet
?2AR is an important drug target and plays a critical role in the relaxation of pulmonary tissues and cardiovascular physiology. We have developed a strategy for classifying various ?2AR conformers as active or inactive states based on binding mode of selected ligands with known activities. Previously distinct conformational states of the ligand’s binding pocket were obtained from a 2.8 µs MD simulation. Snapshots were clustered based on RMSD value of five key residues at the binding site. Clustering analysis yielded a total of 13 distinct conformers to which five agonists four inverse agonists and four antagonists were docked separately using seven different scoring functions. Best ligand poses with the highest score value were selected and evaluated based on their vicinity to five key residues. Poses that were not in this neighborhood were discarded and remaining ones were sorted based on their score. Before treating MD conformers this classification scheme was applied first to both active/inactive state crystal structures for critical assessment. MD conformers found in top five in all scoring functions were selected and assigned to be either active or inactive. Finally selected MD conformers were used to screen a small database to further investigate their discriminatory power. As a result MD conformers performed more selective screening than inactive state crystal structure for antagonists/inverse agonists. Generating alternative conformations of the receptor and classifying them as active or inactive is an important practice in the drug design studies that were often limited to one snapshot obtained from X-ray studies.
Citation Count: 5
Discovery of high affinity ligands for beta(2)-adrenergic receptor through pharmacophore-based high-throughput virtual screening and docking
(Elsevier Science Inc, 2014) Yakar, Rüya; Akten, Ebru Demet
Novel high affinity compounds for human beta(2)-adrenergic receptor (beta(2)-AR) were searched among the clean drug-like subset of ZINC database consisting of 9928465 molecules that satisfy the Lipinski's rule of five. The screening protocol consisted of a high-throughput pharmacophore screening followed by an extensive amount of docking and rescoring. The pharmacophore model was composed of key features shared by all five inactive states of beta(2)-AR in complex with inverse agonists and antagonists. To test the discriminatory power of the pharmacophore model a small-scale screening was initially performed on a database consisting of 117 compounds of which 53 antagonists were taken as active inhibitors and 64 agonists as inactive inhibitors. Accordingly 7.3% of the ZINC database subset (729413 compounds) satisfied the pharmacophore requirements along with 44 antagonists and 17 agonists. Afterwards all these hit compounds were docked to the inactive apo form of the receptor using various docking and scoring protocols. Following each docking experiment the best pose was further evaluated based on the existence of key residues for antagonist binding in its vicinity. After final evaluations based on the human intestinal absorption (HIA) and the blood brain barrier (BBB) penetration properties 62 hit compounds have been clustered based on their structural similarity and as a result four scaffolds were revealed. Two of these scaffolds were also observed in three high affinity compounds with experimentally known K-i values. Moreover novel chemical compounds with distinct structures have been determined as potential beta(2)-AR drug candidates. (C) 2014 Elsevier Inc. All rights reserved.
Citation Count: 5
Distinctive communication networks in inactive states of beta(2)-adrenergic receptor: Mutual information and entropy transfer analysis
(Wiley, 2020) Soğünmez, Nuray; Akten, Ebru Demet
Mutual information and entropy transfer analysis employed on two inactive states of human beta-2 adrenergic receptor (beta(2)-AR) unraveled distinct communication pathways. Previously, a so-called "highly" inactive state of the receptor was observed during 1.5 microsecond long molecular dynamics simulation where the largest intracellular loop (ICL3) was swiftly packed onto the G-protein binding cavity, becoming entirely inaccessible. Mutual information quantifying the degree of correspondence between backbone-C(alpha)fluctuations was mostly shared between intra- and extra-cellular loop regions in the original inactive state, but shifted to entirely different regions in this latest inactive state. Interestingly, the largest amount of mutual information was always shared among the mobile regions. Irrespective of the conformational state, polar residues always contributed more to mutual information than hydrophobic residues, and also the number of polar-polar residue pairs shared the highest degree of mutual information compared to those incorporating hydrophobic residues. Entropy transfer, quantifying the correspondence between backbone-C(alpha)fluctuations at different timesteps, revealed a distinctive pathway directed from the extracellular site toward intracellular portions in this recently exposed inactive state for which the direction of information flow was the reverse of that observed in the original inactive state where the mobile ICL3 and its intracellular surroundings drove the future fluctuations of extracellular regions.
Citation Count: 39
A Docking Study Using Atomistic Conformers Generated via Elastic Network Model for Cyclosporin A/Cyclophilin A Complex
(Taylor & Francis Inc, 2009) Akten, Ebru Demet; Cansu, Sertan; Doruker, Pemra
Anisotropic network model is used to generate a set of distinct conformations for cylophilin A (CypA). The native structure is deformed to different extents along each of the lowest-frequency modes (first 7 modes) both in negative and positive directions. Each node of the elastic network represents either a single atom in the high-resolution model or a single residue in the low-resolution model. Realistic conformations with energies close to or lower than the crystal structure and with satisfactory internal geometry are recovered by energy minimization using implicit solvation model. These conformations are then used for ensemble docking to the ligand cyclosporin A for both a further test of accuracy of generated conformers and exploration of different binding modes. Higher number of correctly docked ligands are obtained for conformations with low deformation factors as a result of lower root mean square distances with respect to crystal structure. Yet Surprisingly the lowest binding energy is obtained for one of the highly deformed conformations as a result of its special contact with arginine side chain oriented towards binding site. Considering the fact that the cyclic ligand's backbone and protein's side chains are held rigid during docking the conformers generated by high- and low-resolution elastic network models are almost equally successful in providing the correct binding mode. The shape of the binding pocket that incorporates crucial interaction sites for hydrogen bond formation is found to be another important determining factor for the success of the dock. Also the small backbone variations of a few angstrom ngstroms in magnitude at the loop regions surrounding the binding pocket can cause amino acids' side chains to be displaced by magnitudes of up to 10 angstrom and therefore have a strong influence on the efficiency of the conformational search during docking.
Citation Count: 0
Docking-based virtual screening for potential activity against bacterial pyruvate kinase
(Springer, 2017) Ergün, Çağla; Akten, Ebru Demet; Doruker, Pemra
[Abstract Not Available]
Citation Count: 1
Drug repositioning to propose alternative modulators for glucocorticoid receptor through structure-based virtual screening
(Taylor & Francis Inc, 2022) Metin, Reyhan; Akten, Ebru Demet
Drug repositioning has recently become one of the widely used drug design approaches in proposing alternative compounds with potentially fewer side effects. In this study, structure-based pharmacophore modelling and docking was used to screen existing drug molecules to bring forward potential modulators for ligand-binding domain of human glucocorticoid receptor (hGR). There exist several drug molecules targeting hGR, yet their apparent side effects still persist. Our goal was to disclose new compounds via screening existing drug compounds to bring forward fast and explicit solutions. The so-called shared pharmacophore model was created using the most persistent pharmacophore features shared by several crystal structures of the receptor. The shared model was first used to screen a small database of 75 agonists and 300 antagonists/decoys, and exhibited a successful outcome in its ability to distinguish agonists from antagonists/decoys. Then, it was used to screen a database of over 5000 molecules composed of FDA-approved, worldwide used and investigational drug compounds. A total of 110 compounds satisfying the pharmacophore requirements were subjected to different docking experiments for further assessment of their binding ability. In the final hit list of 54 compounds which fulfilled all scoring criteria, 19 of them were nonsteroidal and when further investigated, each presented a unique scaffold with little structural resemblance to any known nonsteroidal GR modulators. Independent 100 ns long MD simulations conducted on three selected drug candidates in complex with hGR displayed stable conformations incorporating several hydrogen bonds common to all three compounds and the reference molecule dexamethasone.
Citation Count: 28
Effect of intracellular loop 3 on intrinsic dynamics of human 2-adrenergic receptor
(Bmc, 2013) Ozcan, Ozer; Uyar, Arzu; Doruker, Pemra; Akten, Ebru Demet
Background: To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human beta(2)-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 mu s molecular dynamics (MD) simulation at 310 K. Results: After around 600 ns, the loop model started a transition to a very inactive conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein's binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 angstrom from 11 angstrom, which was further elaborated by docking studies. Conclusions: The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the very inactive state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes.
Citation Count: 0
Effect of Intracellular Loop 3 on Intrinsic Dynamics of Human β2-Adrenergic Receptor
(Cell Press, 2014) Ozcan, Ozer; Uyar, Arzu; Doruker, Pemra; Akten, Ebru Demet
[No Abstract Available]
Citation Count: 15
Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Targets
(Frontiers Media, 2020) Ayyıldız, Merve; Çeliker, Serkan; Özhelvacı, Fatih; Akten, Ebru Demet
Three allosteric glycolytic enzymes, phosphofructokinase, glyceraldehyde-3 phosphate dehydrogenase and pyruvate kinase, associated with bacterial, parasitic and human species, were explored to identify potential allosteric sites that would be used as prime targets for species-specific drug design purposes using a newly developed approach which incorporates solvent mapping, elastic network modeling, sequence and structural alignments. The majority of binding sites detected by solvent mapping overlapped with the interface regions connecting the subunits, thus appeared as promising target sites for allosteric regulation. Each binding site was then evaluated by its ability to alter the global dynamics of the receptor defined by the percentage change in the frequencies of the lowest-frequency modes most significantly and as anticipated, the most effective ones were detected in the vicinity of the well-reported catalytic and allosteric sites. Furthermore, some of our proposed regions intersected with experimentally resolved sites which are known to be critical for activity regulation, which further validated our approach. Despite the high degree of structural conservation encountered between bacterial/parasitic and human glycolytic enzymes, the majority of the newly presented allosteric sites exhibited a low degree of sequence conservation which further increased their likelihood to be used as species-specific target regions for drug design studies.
Citation Count: 2
Information Transfer in Active States of Human ?2-Adrenergic Receptor via Inter-Rotameric Motions of Loop Regions
(Mdpi, 2022) Sogunmez, Nuray; Akten, Ebru Demet
Featured Application Loop regions in beta(2)AR are critical hot spot regions, likely in other GPCRs, and can be used as potential allosteric drug targets. Two independent 1.5 mu s long MD simulations were conducted for the fully atomistic model of the human beta2-adrenergic receptor (beta(2)AR) in a complex with a G protein to investigate the signal transmission in a fully active state via mutual information and transfer entropy based on alpha-carbon displacements and rotameric states of backbone and side-chain torsion angles. Significant correlations between fluctuations in alpha-Carbon displacements were mostly detected between transmembrane (TM) helices, especially TM5 and TM6 located at each end of ICL3 and TM7. Signal transmission across beta(2)-AR was quantified by shared mutual information; a high amount of correspondence was distinguished in almost all loop regions when rotameric states were employed. Moreover, polar residues, especially Arg, made the most contribution to signal transmission via correlated side-chain rotameric fluctuations as they were more frequently observed in loop regions than hydrophobic residues. Furthermore, transfer entropy identified all loop regions as major entropy donor sites, which drove future rotameric states of torsion angles of residues in transmembrane helices. Polar residues appeared as donor sites from which entropy flowed towards hydrophobic residues. Overall, loops in beta(2)AR were recognized as potential allosteric hot spot regions, which play an essential role in signal transmission and should likely be used as potential drug targets.
Citation Count: 2
Intrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human beta(2)-Adrenergic Receptor
(Amer Chemical Soc, 2019) Söğünmez, Nuray; Akten, Ebru Demet
The alternative inactive state of the human beta(2)-adrenergic receptor originally exposed in molecular dynamics simulations was investigated using various analysis tools to evaluate causality between correlated residue-pair fluctuations and suggest allosteric communication pathways. A major conformational shift observed in the third intracellular loop (ICL3) displayed a novel inactive state featuring an inaccessible G protein binding site blocked by ICL3 and an expanded orthosteric ligand binding site. Residue-based mean square fluctuation and stiffness calculations revealed a significant mobility decrease in ICL3 which induced a mobility increase in the remaining loop regions. This indicates conformational entropy loss in one mobile region being compensated by residual intermolecular motions in other mobile regions. Moreover the extent motions decreased and correlations that once existed between transmembrane helices shifted toward regions with increased mobility. Conditional time-delayed cross-correlation analysis identified distinct driver follower relationship profiles. Prior to its packing freely moving ICL3 was markedly driven by transmembrane helix-8 whereas once packed ICL3 controlled future fluctuations of nearby helices. Moreover two transmembrane helices (H5 and H6) started to control future fluctuations of a remote site the extracellular loop ECL2. This clearly suggests that allosteric coupling between extra- and intracellular parts intensified in agreement with the receptor's well recognized feature which is the inverse proportionality between activity and the degree of coupling.
Citation Count: 0
Investigation of allosteric communication pathways in human beta 2-adrenergic receptor
(Wiley-Blackwell, 2015) Akdaş, Başak; Kürkçüoğlu, Özge; Doruker, Pemra; Akten, Ebru Demet
[Abstract Not Available]
Citation Count: 16
Investigation of Allosteric Coupling in Human Beta(2)-Adrenergic Receptor in the Presence of Intracellular Loop 3
(BMC, 2016) Özgür, Canan; Doruker, Pemra; Akten, Ebru Demet
Background: This study investigates the allosteric coupling that exists between the intra- and extracellular parts of human beta(2)-adrenergic receptor (beta(2)-AR) in the presence of the intracellular loop 3 (ICL3) which is missing in all crystallographic experiments and most of the simulation studies reported so far. Our recent 1 mu s long MD run has revealed a transition to the so-called very inactive state of the receptor in which ICL3 packed under the G protein's binding cavity and completely blocked its accessibility to G protein. Simultaneously an outward tilt of transmembrane helix 5 (TM5) caused an expansion of the extracellular ligand-binding site. In the current study we performed independent runs with a total duration of 4 mu s to further investigate the very inactive state with packed ICL3 and the allosteric coupling event (three unrestrained runs and five runs with bond restraints at the ligand-binding site). Results: In all three independent unrestrained runs (each 500 ns long) ICL3 preserved its initially packed/closed conformation within the studied time frame suggesting an inhibition of the receptor's activity. Specific bond restraints were later imposed between some key residues at the ligand-binding site which have been experimentally determined to interact with the ligand. Restraining the binding site region to an open state facilitated ICL3 closure whereas a relatively constrained/closed binding site hindered ICL3 packing. However the reverse operation i.e. opening of the packed ICL3 could not be realized by restraining the binding site region to a closed state. Thus any attempt failed to free the ICL3 from its locked state due to the presence of persistent hydrogen bonds. Conclusions: Overall our simulations indicated that starting with very inactive states the receptor stayed almost irreversibly inhibited which in turn decreased the overall mobility of the receptor. Bond restraints which represented the geometric restrictions caused by ligands of various sizes when bound at the ligand-binding site induced the expected conformational changes in TM5 TM6 and consequently ICL3. Still once ICL3 was packed the allosteric coupling became ineffective due to strong hydrogen bonds connecting ICL3 to the core of the receptor.
Citation Count: 0
Investigation of intrinsic dynamics and allosteric coupling in human beta 2-adrenergic receptor
(Springer, 2017) Özcan, Özer; Özgür, Canan; Doruker, Pemra; Akten, Ebru Demet
[Abstract Not Available]
Citation Count: 8
Ligand-binding affinity of alternative conformers of human beta(2)-adrenergic receptor in the presence of intracellular loop 3 (ICL3) and their potential use in virtual screening studies
(Wiley, 2019) Dilcan, Gonca; Doruker, Pemra; Akten, Ebru Demet
This study investigates the structural distinctiveness of orthosteric ligand-binding sites of several human beta(2) adrenergic receptor (beta(2)-AR) conformations that have been obtained from a set of independent molecular dynamics (MD) simulations in the presence of intracellular loop 3 (ICL3). A docking protocol was established in order to classify each receptor conformation via its binding affinity to selected ligands with known efficacy. This work's main goal was to reveal many subtle features of the ligand-binding site presenting alternative conformations which might be considered as either active- or inactive-like but mostly specific for that ligand. Agonists inverse agonists and antagonists were docked to each MD conformer with distinct binding pockets using different docking tools and scoring functions. Mostly favored receptor conformation persistently observed in all docking/scoring evaluations was classified as active or inactive based on the type of ligand's biological effect. Classified MD conformers were further tested for their ability to discriminate agonists from inverse agonists/antagonists and several conformers were proposed as important targets to be used in virtual screening experiments that were often limited to a single X-ray structure.
Citation Count: 4
Molecular docking study based on pharmacophore modeling for novel PhosphodiesteraseIV ınhibitors
(Wiley-VCH Verlag GmbH, 2012) Cifci, Gulsah; Aviyente, Viktorya; Akten, Ebru Demet
In this study pharmacophore modelling was carried out for novel PhosphodiesteraseIV (PDEIV) inhibitors. A pharmacophore-based virtual screening which resulted in 1959 hit compounds was performed with six chemical databases. The pharmacophore screening was proven to be successful in discriminating active and inactive inhibitors using a set of compounds with known activity obtained from ChEMBL database. Furthermore the Lipinskis rule of five was applied for physicochemical filtering of the hit molecules and this yielded 1840 compounds. Three docking software tools AutoDock 4.0 AutoDock Vina and Gold v5.1 were used for the docking process. All 1840 compounds and the known selective inhibitor rolipram were docked into the active site of the target protein. A total of 234 compounds with all three scoring values higher than those of rolipram were determined with the three docking tools. The interaction maps of 14 potent inhibitors complexed with PDEIV B and D isoforms have been analyzed and seven key residues (Asn 395 Gln 443 Tyr 233 Ile 410 Phe 446 Asp 392 Thr 407) were found to interact with more than 80?% of the potent inhibitors. For each one of the 234 hit compounds using the bound conformation with the highest AutoDock score the interacting residues were determined. 117 out of 234 compounds are found to interact with at least five of the seven key residues and these were selected for further evaluation. The conformation with the highest AutoDock score for each 117 compounds were rescored using the DSX scoring function. This yielded a total of 101 compounds with better score values than the natural ligand rolipram. For ADME/TOX calculations the FAF-Drugs2 server was used and 32 out of 101 compounds were found to be non-toxic.