Kinetic and in silico analysis of thiazolidin-based inhibitors of α-carbonic anhydrase isoenzymes.

Durdagi, Serdar/0000-0002-0426-0905 WOS: 000314531000019 PubMed: 23173744 Carbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, inorganic anions, phenols, salicylic acid derivatives (acting as drug or prodrugs). A novel class of CA inhibitors (CAIs), interacting with the CA isozymes I and II (cytosolic) in a different manner, is reported here. Kinetic measurements allowed us to identify thiazolidin-based compounds as submicromolar-low micromolar inhibitors of these two CA isozymes. Molecular docking studies of a set of such inhibitors within CA I and II active site allowed us to understand the inhibition mechanism. This new class of inhibitors bind differently compared to other classes of inhibitors known to date: they were found between the phenol-binding site, filling thus the middle of the enzyme cavity

Application of 3D QSAR CoMFA/CoMSIA and in silico docking studies on novel renin inhibitors against cardiovascular diseases

For the first time, a set of renin inhibitors were subjected to the 3D QSAR/CoMFA and CoMSIA studies. The utility of renin inhibitors in the treatment of cardiovascular diseases has not been fully explored yet. At the moment, aliskiren is the first and only existing renin inhibitor in the drug market. The performed 3D QSAR/CoMFA and CoMSIA in combination with docking studies included aliskiren and 37 derivatives possessing a wide variety of bioactivity. The obtained results may aid in the design of novel bioactive renin inhibitors

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the headgroup, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC).Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the headgroup. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phasetransition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discusse

In Silico Wirkstoffentwicklung von bioaktiven Cannabinoid- und [60]-Fulleren- Verbindungen

The relationship between conformations of bioactive molecules with their pharmacological profiles has been well established. Only the unique biologically active conformation of a drug molecule can bind to the active site of the receptor. In this thesis, conformational analysis of bioactive compounds at various environments will be discussed. Two categories of molecules were investigated; cannabinoid (CB) analogues and [60]fullerene derivatives. The major structural characteristics of these molecules are: (i) amphiphilicity and (ii) existence of flexible and rigid pharmacophoric segments. Their flexible segments constitute a challenging field for conformational analysis exploring of putative bioactive conformations. In case of CBs, a set of novel Δ8-tetrahydrocannabinol (Δ8-THC) and cannabidiol (CBD) analogues were subjected to three-dimensional quantitative structure-activity relationships (3D-QSAR) studies using comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) methodologies. The high active compound C-1'-dithiolane Δ8-THC analogue AMG3 at the data base was selected as template molecule. Using molecular modeling techniques such as Monte Carlo (MC), molecular dynamics (MD) and grid scan analysis, the putative bioactive conformation of AMG3 in solution was determined. This conformer was used as a template, and CB1 and CB2 pharmacophore models were developed. The availability of homology models of CB1 and CB2 receptors based on rhodopsin has allowed the conformational analysis studies of AMG3 at the binding site of the receptor. Derived low energy conformers of AMG3 at the receptor site have been compared with its in solution conformations. The steroelectronic properties of binding cavities of a receptor model are directly related to the performed molecular model coordinates. In the presented thesis, a homology modeling study based on β2-adrenergic receptor for both CB1 and CB2 receptors was also performed and results were compared with rhodopsin based homology models. Similar binding sites of CB1 and CB2 receptors using rhodopsin based models have been generated using the β2-adrenergic based receptors. The QSAR models were re- generated using putative bioactive conformers of AMG3 at the binding site of the CB1 and CB2 receptors. Relative contributions of steric/electrostatic fields of the 3D QSAR/CoMFA and CoMSIA pharmacophore models have shown that steric effects govern the bioactivity of the compounds, but electrostatic interactions also play an important role. The comparison of derived QSAR models has shown that increasing the complexity level of calculations (mimicking more accurately the biological conditions) was positively affected the obtained statistical result. The optimal QSAR partial least square (PLS) analysis was used as an input in the de novo drug design studies and these simulations provided novel CB analogues with enhanced predicted binding affinities. In case of fullerene derivatives, a series of experimentally reported as well as computationally designed monoadducts and bisadducts of [60]fullerene analogues have been used in order to analyze the binding interactions between fullerene based inhibitors and human immunodeficiency virus type I aspartic protease (HIV-1 PR), employing docking studies. MD simulations of ligand-free and the inhibitor-bound HIV-1 PR systems complemented the above studies and provided proper input structure of HIV-1 PR in docking simulations. The obtained results revealed a different orientation of the β-hairpin flaps at these two systems. In inhibitor bound system, the flaps of the enzyme are pulled in toward the bottom of the active site (the closed form) while, in ligand-free system flaps shifted away from the dual Asp25 catalytic site and this system adopts a semi-open form. The structural analysis of these systems at catalytic and flexible flap regions of the HIV-1 PR through the simulations, assisted in understanding the structural preferences of these regions, as well as, the adopted orientations of fullerene derivatives within the active site of the enzyme. The reported most active fullerene analogue in the data base has been used as template and 3D QSAR models were derived. Based on obtained contour plots and derived PLS analysis, de novo drug design studies were performed in order to propose novel analogues with enhanced binding affinities. Such structures may trigger the interest of medicinal chemists for synthesizing novel HIV-1 PR inhibitors possessing higher bioactivity, considering the urgent need for new anti-HIV drugs.Der Einfluß der Konformation eines bioaktiven Moleküls auf sein pharmakologischen Profil is seit langem bekannt. Nur die biologisch aktive Konformation eines Wirkstoffmoleküls ist in der Lage, eine Bindung mit der aktiven Stelle eines Rezeptors einzugehen. In dieser Arbeit wird die Konformationsanalyse bioaktiver Verbindungen in verschiedenen Umgebungen diskutiert. Zwei verschiedene Molekül-kategorien wurden untersucht: Cannabinoide (CB) sowie [60]Fullerenderivate. Die bedeutsamem strukturellen Merkmale dieser Moleküle sind zum einen, daß sie amphiphil sind und zum zweiten, daß sie sowohl flexible als auch starre pharmakophorische Segmente besitzen. Insbesondere die flexiblen Teile stellen eine Herausforderung für die Konformationsanalyse möglicher bioaktiver Konformationen dar. Im Falle der CB-Verbindungen wurde eine Serie neuer Derivate von Δ8-tetrahydrocannabinol (Δ8-THC) und Cannabidiol (CBD) durch 3-dimensionale Quantitative Struktur- Aktivitätsbeziehungsstudien (3D QSAR) untersucht, einmal mittels vergleichender Molekularfeld-Analyse (CoMFA), als auch mit Methoden, die auf vergeichenden molekularen Ähnlichkeitsindizes (CoMSIA) basieren. Die hochaktive Verbindung AMG3, (C-1'-dithiolan-Δ8-THC) wurde als Template-Molekül aus dem benutzten Datensatz ausgewählt. Die Bestimmung der potentiel bioaktiven Konformation von AMG3 in Lösung erfolgte durch verschiedene molekulare Modellierungstechniken: Monte Carlo (MC), Molküldynamik (MD) sowie Gitterscananalysen. Das erhaltene Konformer wurde dann als Template weiter benutzt, und CB1 und CB2 Pharmakophor-Modelle wurden entwickelt. Verfügbare Homologiemodelle von CB1 und CB2, die auf Rhodopsin basieren, ermöglichten die Konformationsanalyse von AMG3 an der Bindungsstelle der Rezeptoren. Die erhaltenenen energetisch begünstigten Konformere von AMG3 an der Bindungsstelle wurden mit den entsprechenden Konformationen in Lösung verglichen. Die stereoelektronischen Eigenschaften der Bindungskavitäten eines Rezeptormodells stehen in direktem Zusammenhang mit den benutzten molekularen Koordinaten des Modells. In der vorliegenden Arbeit wurde auch eine auf dem β2-Adrenorezeptor basierende Homologie-Modellstudie für die CB1 und CB2-Rezeptoren durchgeführt, und mit den Ergebnissen des mit dem auf dem Rhodopsin-Rezeptor basierten Homologiemodells verglichen. Ähnliche Bindungsstellen in den CB1 und CB2-Rezeptoren wurden sowohl von den auf Rhodopsin basierten Modellen als auch von auf β2-Adrenorezeptor-basierten Modellen erzeugt. Die 3D QSAR Modelle wurden regeneriert mithilfe von potentiellen Konformeren von AMG3 an den Bindungsstellen der CB1- und CB2-Rezeptoren. Die von den 3D QSAR/CoMFA bzw: CoMSIA Pharmakophormodellen berechneten relativen Beiträge der sterischen und elektrostatischen Felder zeigten, daß die Bioaktivität der Verbindungen hauptsächlich durch sterische Effekte bestimmt wird, obwohl elektrostatische Effekte auch eine Rolle spielen. Ein Vergleich entsprechender QSAR Modelle zeigte, daß die erhaltenen statistischen Resultate positiv beeinflußt wurden, wenn die Komplexität der Rechnungen im Sinne einer realistischeren Modellierung des umgebenden Mediums erhöht wurde. Die optimale QSAR Analyse mit partieller minimierter quadratischer Abweichung (PLS) wurde in Arbeiten zur de novo Wirkstoff- Entwicklung benutzt, und haben zur Entwicklung neuer Verbindungen mit verbesserten vorhergesagten Bindungsaktivitäten geführt. Im Fall der Fullerenderivate wurde eine Serie von experimentell bekannten als auch von theoretisch entwickelten Mono- und Bisaddukten von [60]-Fullerenderivaten ausgewählt und in Bezug auf die Bindungswechselwirkungen zwischen Fullerenbasierten Inhibitoren und Immunodefizienzvirus Typ I Endopeptidase (HIV-1 PR) mithilfe von Dockingsstudien analysiert. MD-Simulationen des freien als auch des Inhibitor-gebundenen HIV-1 PR Systems ergänzten die genannten Studien und lieferten geeignete Startstrukturen für die Dockingssimulationen von HIV-1 PR. Die erhaltenen Ergebnisse zeigen eine unterschiedliche Orienterung der sogennannten β-Haarnadel Laschen zwischen den beiden Systemem. In der Form mit angebundenem Fullereninhibitor werden die Laschen in Richtung des Bodens des aktiven Bereichs hin gezogen (sogenannte geschlossene Form), während die freie Form von HIV-1 PR eine halboffene Konformation bevorzugt. Die Strukturanalyse der katalytischen Segemente als auch der flexiblen Laschenregionen im Verlauf der Simulation von HIV-1 PR unterstützt das Verständnis sowohl der strukturellen Präferenzen dieser Regionen, als auch der von den Fullerenverbindungen eingenommenen Orientierungen innerhalb der aktiven Kavität des Enzyms. Die Fullerenverbindung aus der Datenbank, die sich als die aktivste erwies, wurde anschließend als Template ausgewählt zur Erstellung von 3D QSAR-Modellen. Die damit erhaltenen Konturoberflächen sowie die Ergebnisse der PLS-Analyse wurden für de novo Wirkstoffentwickungsstudien benutzt, mit dem Ziel, neue Fullerenderivate mit höherem Bindungsaktivitäten vorzuschlagen. Solche Moleküle können für den medizinischen Chemiker zur Synthese neuer HIV-1 PR Inhibitoren mit höhere Bioaktivität von Interesse sein, und damit auf der Suche nach dringend benötigten neuen Anti-HIV Wirkstoffen von Bedeutung sein

Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p

AT1 antagonists: a patent review (2008 - 2012)

Introduction: For two decades a class of pharmaceutical molecules with proved beneficial therapeutic properties, especially in hypertension, has been introduced in the market aiming to specifically prevent the detrimental effects of the peptide hormone Angiotensin II at the AT1 receptor. The prototype of this class was losartan and based on its structure, several drugs were launched and also called &apos;Sartans&apos;. New structural features on these molecules can provide multi-target properties in the RAS or other systems. New methodologies were developed for the treatment of hypertension utilizing either AT1 antagonists alone or as cocktails. Areas covered: In this review article, authors aim to cover information provided by patents of the years 2008 - 2012. The rationale of writing this review article is to cover the most important patents which can forward the field with new important discoveries. Expert opinion: From the patent investigation it is clear that new areas on the subject are still offered for new discoveries. New structural features can be still considered in the synthetic compounds that can advance the knowledge and beneficial effects on diseases related to Angiotensin II and AT1 receptor. There is era also for new formulations (i.e., cyclodextrins, polymers and liposomes). The multitarget approach can be further strengthened and more combinations can be sought in the rational drug design for seeking cocktails. Furthermore, the revealing of the complexity of the RAS offers new avenues for novel targets and this must not be overlooked

ANN-based Drug-isolate-fold-change model predicting the resistance profiles of HIV-1 protease inhibitors

: Drug resistance is a primary barrier to effective treatments of HIV/AIDS. Calculating quantitative relations between genotype and phenotype observations for each inhibitor with cell-based assays requires time and money consuming experiments. Machine learning models are good options for tackling these problems by generalizing the available data with suitable linear or nonlinear mappings. The main aim of this paper is to construct drug isolate fold change (DIF)-based artificial neural network (ANN) models for estimating the resistance potential of molecules inhibiting the HIV-1 protease (PR) enzyme. Throughout the study, seven of eight protease inhibitors (PIs) have been included in the training set and the remaining ones in the test set. Using the 7-in 1-out procedure, eight ANN models have been produced to measure the learning capacity of models from the descriptors of the inhibitors. The mean value of eight ANN models for unseen inhibitors is and 95% confidence interval (CI) is Predicting the fold change resistance for hundreds of isolates allowed for robust comparison of drug pairs. These eight models have predicted the drug resistance tendencies of each inhibitor pair with the mean 2D correlation coefficient 0.933 and 95% CI A classification problem has been created to predict the ordered relationship of the PIs and the mean accuracy, sensitivity and specificity values are obtained as 0.954, 0.791 and 0.791, respectively. The currently derived ANN models can accurately predict the drug resistance tendencies of PI pairs, and this observation could help test new inhibitors with various isolates