berna dogan - Academia.edu (original) (raw)
Papers by berna dogan
Journal of Molecular Graphics and Modelling, 2022
Glioblastoma Multiforme (GBM) is the most aggressive brain tumor and classified as one of the dea... more Glioblastoma Multiforme (GBM) is the most aggressive brain tumor and classified as one of the deadliest cancers. The current treatment plans for GBM remains to be ineffective because of its rapid progress and inability of the drugs used to cross the blood-brain barrier (BBB). Thus, developing more effective and potent medicines for GBM are needed. There have been several reports demonstrating that CAPE presents reasonably good anti-cancer activity in certain cancer cell lines and can penetrate the blood-brain barrier. Accordingly, in this study we synthesized several novel CAPE analogs with the addition of more druggable handles and solubilizing entities and subsequently evaluated their in vitro therapeutic efficacies in GBM cell lines (T98G and LN229). The most potent compound was then examined extensively and results showed that the 50 μM novel CAPE analog (compound 10) significantly decreases the viability of both T98G and LN229 GBM cells as compared to CAPE itself. Moreover, the compound 10 was not cytotoxic to healthy human cells (fibroblast-like mesenchymal stem cells) at the same concentration. Apoptotic (32.8%, and 44.6%) cell populations were detected in the compound 10 treated groups for LN229 and T98G, respectively. As an indication of apotosis, significantly increased PARP cleavage was detected in compound 10 versus CAPE treated LN229. In addition, we conducted molecular docking and molecular dynamics (MD) simulations studies on certain targets playing roles on GBM disease pathway such as NF-κB, EGFR, TNF-α, ERK2, PAPR1, hCA IX and hCA XII. Our findings demonstrated that designed CAPE analogs have anti-cancer activity on GBM cells and in silico studies also demonstrate the inhibitory ability of suggested compounds via interactions with critical residues in binding pockets of studied targets. Here, we suggest the novel CAPE analog to study further against GBM. Therefore, identification of the compound related molecular signature may provide more to understand the mechanism of action.
Frontiers in Chemistry, 2020
indole and indol derivatives. Around 2700 compounds are filtered based on "cancer-QSAR" model and... more indole and indol derivatives. Around 2700 compounds are filtered based on "cancer-QSAR" model and are then docked into BCL-2. Short MD simulations are performed for the top-docking poses for each compound in complex with BCL-2. The complexes are again ranked based on their MM/GBSA values to select hit molecules for further long MD simulations and in vitro studies. In total, seven molecules are subjected to biological activity tests in various human cancer cell lines as well as Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay. Inhibitory concentrations are evaluated, and biological activities and apoptotic potentials are assessed by cell culture studies. Four molecules are found to be limiting the proliferation capacity of cancer cells while increasing the apoptotic cell fractions.
Journal of Biomolecular Structure and Dynamics, 2019
Abstract Naringenin is considered as an important flavonoid in phytochemistry because of its impo... more Abstract Naringenin is considered as an important flavonoid in phytochemistry because of its important effect on cancer chemoprevention. Unfortunately its poor solubility has restricted its therapeutic applications. In this study, an efficient water-soluble fluorescent calix[4]arene (compound 5) was synthesized as host macromolecule to increase solubility and cytotoxicity in cancer cells of water-insoluble naringenin as well as to clarify localization of naringenin into the cells. Complex formed by host–guest interaction between compound 5 and naringenin was analyzed with UV–visible, fluorescence, FTIR spectroscopic techniques and molecular modeling studies. Stern–Volmer analysis showed binding constant value of Ksv 3.5 × 107 M−1 suggesting strong interaction between host and guest. Binding capacity shows 77% of naringenin was loaded on compound 5. Anticarcinogenic effects of naringenin complex were evaluated on human colorectal carcinoma cells (DLD-1) and it was found that 5-naringenin complex inhibits proliferation of DLD-1 cells 3.4-fold more compared to free naringenin. Fluorescence imaging studies show 5-naringenin complex was accumulated into the cytoplasm instead of the nucleus. Increased solubility and cytotoxicity of naringenin with fluorescent calix[4]arene makes it one of the potential candidates as a therapeutic enhancer. For deep understanding of host–guest interaction mechanisms, complementary multiscale molecular modeling studies were also carried out. Communicated by Ramaswamy H. Sarma
PeerJ
Drug resistance is a primary barrier to effective treatments of HIV/AIDS. Calculating quantitativ... more 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 study is to construct drug isolate fold (DIF) change-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. We have obtained 11,803 genotype-phenotype data points for eight PIs from Stanford HIV drug resistance database. Using the leave-one-out (LVO) procedure, eight ANN models have been produced to measure the learning capacity of models from the descript...
Data includes all of the trajectories (2000) of classical all-atom molecular dynamics (MD) simula... more Data includes all of the trajectories (2000) of classical all-atom molecular dynamics (MD) simulations of lopinavir at the binding pocket of SARS-CoV2 main protease target. In order to decrease the size of the file only protein and ligand trajectories were provided. Simulation has been performed with Desmond. Protein–ligand complexes were obtained by Glide/SP docking program. Complex was placed in the cubic boxes with explicit TIP3P water models that have 10.0 Å thickness from surfaces of protein. The system is neutralized by adding counter ions, and salt solution of 0.15M NaCl was also used to adjust the concentration of the systems. The long-range electrostatic interactions were calculated by the particle mesh Ewald method. A cutoff<br> radius of 9.0 Å was used for both van der Waals and Coulombic interactions. The temperature was set as 310K initially, and Nose–Hoover thermostat was used for adjustment. Martyna–Tobias–Klein protocol was employed to control the pressure, whi...
Bioorganic Chemistry
In the present study, new tacrine derivatives containing carbamate group were synthesized and the... more In the present study, new tacrine derivatives containing carbamate group were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition activities were evaluated. All synthesized compounds inhibited both cholinesterases at nanomolar level. Among them, ((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl(3-nitrophenyl) carbamate (6k) showed the best inhibitor activity against AChE and BuChE with IC50 value of 22.15 nM and 16.96 nM, respectively. The calculated selectivity index revealed that the synthesized compounds (exclude 6l) have stronger inhibitory activity against BuChE than AChE. The most selective compound was 2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl(4-methoxyphenyl)-carbamate (6b) with the selectivity index of 0.12. Molecular modeling approaches were employed to understand the interaction between the synthesized compounds and proteins. As carbamate derivatives can act as pseudo-irreversible inhibitors of AChE and BuChE, covalent docking approaches was applied to determine the binding modes of novel compounds at binding sites of cholinesterase enzymes.
The COVID19 pandemic has resulted in 25+ million reported infections and nearly 850.000 deaths. R... more The COVID19 pandemic has resulted in 25+ million reported infections and nearly 850.000 deaths. Research to identify effective therapies for COVID19 includes: i) designing a vaccine as future protection; ii) structure-based drug design; and iii) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determined two apo structures of Severe Acute Respiratory Syndrome CoronaVirus-2 main protease at ambienttemperature by Serial Femtosecond X-ray crystallography. We employed detailed molecular simulations of selected known main protease inhibitors with the structures and compared binding modes and energies. The combined structural biology and molecular modeling studies not only reveal the dynamics of small molecules targeting main protease but will also provide invaluable opportunities for drug repurposing and structure-based drug design studies against SARS-CoV-2.One Sentence SummaryRadiation-damage-free high-reso...
In this work, a computational protocol is proposed to predict the dissolution rates of molecular ... more In this work, a computational protocol is proposed to predict the dissolution rates of molecular crystals that found usages in pharmaceutical industry to speed up the drug discovery process
Molecular Informatics
In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clin... more In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS-CoV-2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top-100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS-CoV-2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration-dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.
Molecular Informatics
Current antiretroviral therapies against HIV involve the usage of at least two drugs that target ... more Current antiretroviral therapies against HIV involve the usage of at least two drugs that target different stages of HIV life cycle. However, potential drug interactions and side effects pose a problem. A promising concept for complex disease treatment is ‘one molecule‐multiple target’ approach to overcome undesired effects of multiple drugs. Additionally, it is beneficial to consider drug re‐purposing due to the cost of taking a drug into the market. Taking these into account, here potential anti‐HIV compounds are suggested by virtually screening small approved drug molecules and clinical candidates. Initially, binary QSAR models are used to predict the therapeutic activity of around 7900 compounds against HIV and to predict the toxicity of molecules with high therapeutic activities. Selected compounds are considered for molecular docking studies against two targets, HIV‐1 protease enzyme, and chemokine co‐receptor CCR5. The top docking poses for all 549 molecules are then subjected to short (1 ns) individual molecular dynamics (MD) simulations and they are ranked based on their calculated relative binding free energies. Finally, 25 molecules are selected for long (200 ns) MD simulations, and 5 molecules are suggested as promising multi‐target HIV agents. The results of this study may open new avenues for the designing of new dual HIV‐1 inhibitor scaffolds.
New Journal of Chemistry
Although quercetin is an effective bioactive compound preventing the progress of several human ca... more Although quercetin is an effective bioactive compound preventing the progress of several human cancers, its impact is reduced due to low bioavailability.
ChemMedChem
The ubiquitin‐specific protease 7 (USP7) is a highly promising well‐validated target for a variet... more The ubiquitin‐specific protease 7 (USP7) is a highly promising well‐validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti‐proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti‐cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post‐MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug‐like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1‐ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure‐based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field.
There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing i... more There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged preclinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs againstCOVID-19 due to its pivotal role in the replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical inve...
Current Opinion in Structural Biology
Membrane receptors couple signaling pathways using various mechanisms. G Protein-Coupled Receptor... more Membrane receptors couple signaling pathways using various mechanisms. G Protein-Coupled Receptors (GPCRs) represent the largest class of membrane proteins involved in signal transduction across the biological membranes. They are essential targets for cell signaling and are of great commercial interest to the pharmaceutical industry. Recent advances made in molecular biology and computational chemistry offer a range of simulation and multiscale modeling tools for the definition and analysis of protein-ligand, protein-protein, and protein-membrane interactions. The development of new techniques on statistical methods and free energy simulations help to predict novel optimal ligands, G protein specificity and oligomerization. The identification of the ligand-binding activation mechanisms and atomistic determinants as well as the interactions of intracellular binding partners that bind to GPCR targets in different coupling states will provide greater safety in human life. In this review, recent approaches and applications of multiscale simulations on GPCRs were highlighted.
Biophysical Journal
various peptide concentrations and pH levels. The absorbance transitions are sensitive to the for... more various peptide concentrations and pH levels. The absorbance transitions are sensitive to the formation of the electronically conductive J-aggregate, allowing for rapid spectroscopic identification. Fluorescence spectroscopy, circular dichroism, and dynamic light scattering were also used to assess J-aggregate formation. The peptides were shown to induce the formation of J-aggregates up to solution pH 3.0, but maintains the ability to bind porphyrin at neutral pH. Notably, the peptides were shown to adopt an unstructured conformation at low pH but become somewhat helical at neutral pH. Studies of mixed peptide binding stoichiometry indicate formation of complementary heterooligomers that retain their porphyrin-binding capabilities and produce an additional binding site at their junction. These results have implications for the design of photoelectronically active biomaterials.
Chemical Physics Letters, 2016
Abstract The correlation between in vitro dissolution rates and the efficiency of drug formulatio... more Abstract The correlation between in vitro dissolution rates and the efficiency of drug formulations establishes an opportunity for accelerated drug development. Using in silico methods to predict the dissolution rates bears the prospect of further efficiency gains by avoiding the actual synthesis of candidate formulations. Here, we present a computational protocol that achieves such prediction for molecular crystals at low undersaturation. The protocol exploits the classic spiral dissolution model to minimize the number of material parameters that require explicit molecular simulations. Comparison to available data for acetylsalicylic acid and alpha lactose monohydrate indicates a tunable accuracy within one order of magnitude.
The propagation kinetics of ethyl methacrylate (EMA) and ethyl a-hydroxy methacrylate (EHMA) has ... more The propagation kinetics of ethyl methacrylate (EMA) and ethyl a-hydroxy methacrylate (EHMA) has been subject to a computational study to understand their free radical polymerization (FRP) behavior in bulk and in solution using Density Functional Theory (DFT). The propagation of EHMA is studied in ethanol and toluene to assess the effect of hydrogen-bonding solvents on FRP of monomers with ahydroxy functionality. Although EMA and EHMA resemble each other in structure, EHMA propagates faster in bulk due to the presence of intermolecular hydrogen-bonds, which tend to facilitate the approach of the propagating species. This falls in contrast with the experimentally observed lower propagation rates of EHMA in ethanol compared to toluene. Calculations show that the 2.28 rate acceleration in toluene is governed by the ratio of the pre-exponential factors, which reflect the entropies of activation, in both media. The polar protic solvent ethanol has a disruptive effect via hydrogenbonding on the 6-membered ring shape of EHMA monomers thus decreasing the entropy of activation of the reaction. In the case of toluene, there are no special interactions with the hydrophobic solvent, the entropy of activation is higher than in ethanol.
Journal of Molecular Graphics and Modelling, 2022
Glioblastoma Multiforme (GBM) is the most aggressive brain tumor and classified as one of the dea... more Glioblastoma Multiforme (GBM) is the most aggressive brain tumor and classified as one of the deadliest cancers. The current treatment plans for GBM remains to be ineffective because of its rapid progress and inability of the drugs used to cross the blood-brain barrier (BBB). Thus, developing more effective and potent medicines for GBM are needed. There have been several reports demonstrating that CAPE presents reasonably good anti-cancer activity in certain cancer cell lines and can penetrate the blood-brain barrier. Accordingly, in this study we synthesized several novel CAPE analogs with the addition of more druggable handles and solubilizing entities and subsequently evaluated their in vitro therapeutic efficacies in GBM cell lines (T98G and LN229). The most potent compound was then examined extensively and results showed that the 50 μM novel CAPE analog (compound 10) significantly decreases the viability of both T98G and LN229 GBM cells as compared to CAPE itself. Moreover, the compound 10 was not cytotoxic to healthy human cells (fibroblast-like mesenchymal stem cells) at the same concentration. Apoptotic (32.8%, and 44.6%) cell populations were detected in the compound 10 treated groups for LN229 and T98G, respectively. As an indication of apotosis, significantly increased PARP cleavage was detected in compound 10 versus CAPE treated LN229. In addition, we conducted molecular docking and molecular dynamics (MD) simulations studies on certain targets playing roles on GBM disease pathway such as NF-κB, EGFR, TNF-α, ERK2, PAPR1, hCA IX and hCA XII. Our findings demonstrated that designed CAPE analogs have anti-cancer activity on GBM cells and in silico studies also demonstrate the inhibitory ability of suggested compounds via interactions with critical residues in binding pockets of studied targets. Here, we suggest the novel CAPE analog to study further against GBM. Therefore, identification of the compound related molecular signature may provide more to understand the mechanism of action.
Frontiers in Chemistry, 2020
indole and indol derivatives. Around 2700 compounds are filtered based on "cancer-QSAR" model and... more indole and indol derivatives. Around 2700 compounds are filtered based on "cancer-QSAR" model and are then docked into BCL-2. Short MD simulations are performed for the top-docking poses for each compound in complex with BCL-2. The complexes are again ranked based on their MM/GBSA values to select hit molecules for further long MD simulations and in vitro studies. In total, seven molecules are subjected to biological activity tests in various human cancer cell lines as well as Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) assay. Inhibitory concentrations are evaluated, and biological activities and apoptotic potentials are assessed by cell culture studies. Four molecules are found to be limiting the proliferation capacity of cancer cells while increasing the apoptotic cell fractions.
Journal of Biomolecular Structure and Dynamics, 2019
Abstract Naringenin is considered as an important flavonoid in phytochemistry because of its impo... more Abstract Naringenin is considered as an important flavonoid in phytochemistry because of its important effect on cancer chemoprevention. Unfortunately its poor solubility has restricted its therapeutic applications. In this study, an efficient water-soluble fluorescent calix[4]arene (compound 5) was synthesized as host macromolecule to increase solubility and cytotoxicity in cancer cells of water-insoluble naringenin as well as to clarify localization of naringenin into the cells. Complex formed by host–guest interaction between compound 5 and naringenin was analyzed with UV–visible, fluorescence, FTIR spectroscopic techniques and molecular modeling studies. Stern–Volmer analysis showed binding constant value of Ksv 3.5 × 107 M−1 suggesting strong interaction between host and guest. Binding capacity shows 77% of naringenin was loaded on compound 5. Anticarcinogenic effects of naringenin complex were evaluated on human colorectal carcinoma cells (DLD-1) and it was found that 5-naringenin complex inhibits proliferation of DLD-1 cells 3.4-fold more compared to free naringenin. Fluorescence imaging studies show 5-naringenin complex was accumulated into the cytoplasm instead of the nucleus. Increased solubility and cytotoxicity of naringenin with fluorescent calix[4]arene makes it one of the potential candidates as a therapeutic enhancer. For deep understanding of host–guest interaction mechanisms, complementary multiscale molecular modeling studies were also carried out. Communicated by Ramaswamy H. Sarma
PeerJ
Drug resistance is a primary barrier to effective treatments of HIV/AIDS. Calculating quantitativ... more 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 study is to construct drug isolate fold (DIF) change-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. We have obtained 11,803 genotype-phenotype data points for eight PIs from Stanford HIV drug resistance database. Using the leave-one-out (LVO) procedure, eight ANN models have been produced to measure the learning capacity of models from the descript...
Data includes all of the trajectories (2000) of classical all-atom molecular dynamics (MD) simula... more Data includes all of the trajectories (2000) of classical all-atom molecular dynamics (MD) simulations of lopinavir at the binding pocket of SARS-CoV2 main protease target. In order to decrease the size of the file only protein and ligand trajectories were provided. Simulation has been performed with Desmond. Protein–ligand complexes were obtained by Glide/SP docking program. Complex was placed in the cubic boxes with explicit TIP3P water models that have 10.0 Å thickness from surfaces of protein. The system is neutralized by adding counter ions, and salt solution of 0.15M NaCl was also used to adjust the concentration of the systems. The long-range electrostatic interactions were calculated by the particle mesh Ewald method. A cutoff<br> radius of 9.0 Å was used for both van der Waals and Coulombic interactions. The temperature was set as 310K initially, and Nose–Hoover thermostat was used for adjustment. Martyna–Tobias–Klein protocol was employed to control the pressure, whi...
Bioorganic Chemistry
In the present study, new tacrine derivatives containing carbamate group were synthesized and the... more In the present study, new tacrine derivatives containing carbamate group were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition activities were evaluated. All synthesized compounds inhibited both cholinesterases at nanomolar level. Among them, ((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl(3-nitrophenyl) carbamate (6k) showed the best inhibitor activity against AChE and BuChE with IC50 value of 22.15 nM and 16.96 nM, respectively. The calculated selectivity index revealed that the synthesized compounds (exclude 6l) have stronger inhibitory activity against BuChE than AChE. The most selective compound was 2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl(4-methoxyphenyl)-carbamate (6b) with the selectivity index of 0.12. Molecular modeling approaches were employed to understand the interaction between the synthesized compounds and proteins. As carbamate derivatives can act as pseudo-irreversible inhibitors of AChE and BuChE, covalent docking approaches was applied to determine the binding modes of novel compounds at binding sites of cholinesterase enzymes.
The COVID19 pandemic has resulted in 25+ million reported infections and nearly 850.000 deaths. R... more The COVID19 pandemic has resulted in 25+ million reported infections and nearly 850.000 deaths. Research to identify effective therapies for COVID19 includes: i) designing a vaccine as future protection; ii) structure-based drug design; and iii) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determined two apo structures of Severe Acute Respiratory Syndrome CoronaVirus-2 main protease at ambienttemperature by Serial Femtosecond X-ray crystallography. We employed detailed molecular simulations of selected known main protease inhibitors with the structures and compared binding modes and energies. The combined structural biology and molecular modeling studies not only reveal the dynamics of small molecules targeting main protease but will also provide invaluable opportunities for drug repurposing and structure-based drug design studies against SARS-CoV-2.One Sentence SummaryRadiation-damage-free high-reso...
In this work, a computational protocol is proposed to predict the dissolution rates of molecular ... more In this work, a computational protocol is proposed to predict the dissolution rates of molecular crystals that found usages in pharmaceutical industry to speed up the drug discovery process
Molecular Informatics
In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clin... more In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS-CoV-2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top-100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS-CoV-2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration-dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.
Molecular Informatics
Current antiretroviral therapies against HIV involve the usage of at least two drugs that target ... more Current antiretroviral therapies against HIV involve the usage of at least two drugs that target different stages of HIV life cycle. However, potential drug interactions and side effects pose a problem. A promising concept for complex disease treatment is ‘one molecule‐multiple target’ approach to overcome undesired effects of multiple drugs. Additionally, it is beneficial to consider drug re‐purposing due to the cost of taking a drug into the market. Taking these into account, here potential anti‐HIV compounds are suggested by virtually screening small approved drug molecules and clinical candidates. Initially, binary QSAR models are used to predict the therapeutic activity of around 7900 compounds against HIV and to predict the toxicity of molecules with high therapeutic activities. Selected compounds are considered for molecular docking studies against two targets, HIV‐1 protease enzyme, and chemokine co‐receptor CCR5. The top docking poses for all 549 molecules are then subjected to short (1 ns) individual molecular dynamics (MD) simulations and they are ranked based on their calculated relative binding free energies. Finally, 25 molecules are selected for long (200 ns) MD simulations, and 5 molecules are suggested as promising multi‐target HIV agents. The results of this study may open new avenues for the designing of new dual HIV‐1 inhibitor scaffolds.
New Journal of Chemistry
Although quercetin is an effective bioactive compound preventing the progress of several human ca... more Although quercetin is an effective bioactive compound preventing the progress of several human cancers, its impact is reduced due to low bioavailability.
ChemMedChem
The ubiquitin‐specific protease 7 (USP7) is a highly promising well‐validated target for a variet... more The ubiquitin‐specific protease 7 (USP7) is a highly promising well‐validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti‐proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti‐cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post‐MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug‐like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1‐ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure‐based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field.
There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing i... more There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged preclinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs againstCOVID-19 due to its pivotal role in the replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical inve...
Current Opinion in Structural Biology
Membrane receptors couple signaling pathways using various mechanisms. G Protein-Coupled Receptor... more Membrane receptors couple signaling pathways using various mechanisms. G Protein-Coupled Receptors (GPCRs) represent the largest class of membrane proteins involved in signal transduction across the biological membranes. They are essential targets for cell signaling and are of great commercial interest to the pharmaceutical industry. Recent advances made in molecular biology and computational chemistry offer a range of simulation and multiscale modeling tools for the definition and analysis of protein-ligand, protein-protein, and protein-membrane interactions. The development of new techniques on statistical methods and free energy simulations help to predict novel optimal ligands, G protein specificity and oligomerization. The identification of the ligand-binding activation mechanisms and atomistic determinants as well as the interactions of intracellular binding partners that bind to GPCR targets in different coupling states will provide greater safety in human life. In this review, recent approaches and applications of multiscale simulations on GPCRs were highlighted.
Biophysical Journal
various peptide concentrations and pH levels. The absorbance transitions are sensitive to the for... more various peptide concentrations and pH levels. The absorbance transitions are sensitive to the formation of the electronically conductive J-aggregate, allowing for rapid spectroscopic identification. Fluorescence spectroscopy, circular dichroism, and dynamic light scattering were also used to assess J-aggregate formation. The peptides were shown to induce the formation of J-aggregates up to solution pH 3.0, but maintains the ability to bind porphyrin at neutral pH. Notably, the peptides were shown to adopt an unstructured conformation at low pH but become somewhat helical at neutral pH. Studies of mixed peptide binding stoichiometry indicate formation of complementary heterooligomers that retain their porphyrin-binding capabilities and produce an additional binding site at their junction. These results have implications for the design of photoelectronically active biomaterials.
Chemical Physics Letters, 2016
Abstract The correlation between in vitro dissolution rates and the efficiency of drug formulatio... more Abstract The correlation between in vitro dissolution rates and the efficiency of drug formulations establishes an opportunity for accelerated drug development. Using in silico methods to predict the dissolution rates bears the prospect of further efficiency gains by avoiding the actual synthesis of candidate formulations. Here, we present a computational protocol that achieves such prediction for molecular crystals at low undersaturation. The protocol exploits the classic spiral dissolution model to minimize the number of material parameters that require explicit molecular simulations. Comparison to available data for acetylsalicylic acid and alpha lactose monohydrate indicates a tunable accuracy within one order of magnitude.
The propagation kinetics of ethyl methacrylate (EMA) and ethyl a-hydroxy methacrylate (EHMA) has ... more The propagation kinetics of ethyl methacrylate (EMA) and ethyl a-hydroxy methacrylate (EHMA) has been subject to a computational study to understand their free radical polymerization (FRP) behavior in bulk and in solution using Density Functional Theory (DFT). The propagation of EHMA is studied in ethanol and toluene to assess the effect of hydrogen-bonding solvents on FRP of monomers with ahydroxy functionality. Although EMA and EHMA resemble each other in structure, EHMA propagates faster in bulk due to the presence of intermolecular hydrogen-bonds, which tend to facilitate the approach of the propagating species. This falls in contrast with the experimentally observed lower propagation rates of EHMA in ethanol compared to toluene. Calculations show that the 2.28 rate acceleration in toluene is governed by the ratio of the pre-exponential factors, which reflect the entropies of activation, in both media. The polar protic solvent ethanol has a disruptive effect via hydrogenbonding on the 6-membered ring shape of EHMA monomers thus decreasing the entropy of activation of the reaction. In the case of toluene, there are no special interactions with the hydrophobic solvent, the entropy of activation is higher than in ethanol.