Kayhan Bolelli

Public health is still under attack by a worldwide pandemic caused by a coronavirus which is known to cause mainly respiratory and enteric disease in humans. Currently, still limited knowledge exists on the exact action mechanism and biology of SARS‒CoV‒2 although there are several effective vaccines and antiviral treatment. Besides, there is a considerable amount of 3D protein structures for SARS–CoV–2, related to its main protease resolved by X–ray diffraction. Here, we used molecular docking strategy to predict possible inhibitory activities of flavonoids on SARS–CoV–2 Mpro enzyme. For this, 800 flavonoids were retrieved from the ZINC database. Results suggested that avicularin was the lead flavonoid which docked to Mpro with the best binding energy. However, most of flavonoids showed H–bond interactions with Hie–41 and Cys–145 catalytic dyad, which were important residues for the catalytic activity of SARS–CoV–2 Mpro. Strong hydrogen bonding (2.36 Å) with Sγ atom of Cys145 residue was observed. This might suggest an initial formation of covalent bonding. Findings showed that selected flavonoids could be promising inhibitors of this enzyme and have the potential for future therapeutic drugs against COVID–19 after immediate experimental validation and clinical approvals.

Purpose As of July 2022, the COVID-19 pandemic has affected over 555 million worldwide confirmed cases and caused more than 6.3 million deaths. The studies showed that the D-dimer levels were increased in non-survivors compared to survivors and heparin treatment has begun to be administered to the patients in severe clinics. As we knew that the entrance of SARS-CoV-2 to the host cell needs to be facilitated by host proteases; we published our hypothesis that heparin as a serine protease inhibitor may block the interaction between spike protein receptor-binding domain and host proteases. In our study, we aimed to investigate the interactions between not only heparins but also other antiplatelet and anticoagulant drugs including fondaparinux. Methods In this study, docking studies were carried out to evaluate the interactions between low molecular weight heparins (LMWHs) (enoxaparin, dalteparin, tinzaparin), direct oral anticoagulant, and antiplatelet drugs with host proteases. Molecular docking studies were performed by using Schrödinger molecular modeling software. 3D structures of the ligands were obtained from the 2D structures by assigning the OPLS-2005 force field using the Maestro 12.7. The 3D crystal structure of the furin complexed with an inhibitor, 2,5-dideoksistreptamin derivative, was extracted from the Protein Data Bank (PDB ID: 5MIM). Docking studies were carried out using the Grid-based Ligand Docking with Energetics module of the Schrödinger Software. Results The docking studies revealed that fondaparinux was the most relevant molecule to interact with furin with a docking score of − 12.74. It showed better interaction than the natural ligand of furin with an increased score compared to the docking score of − 8.155 of the natural ligand. AnaGA*IsA structure representing LMWH structure has shown a docking score of − 11.562 which was also better than the score of the natural ligand of furin. Conclusion Our findings have shown that LMWHs and fondaparinux can be used for their possible antiviral effects in COVID-19 patients. Our results have shown that in accordance with heparin and LMWH, fondaparinux can also be a candidate for “drug repurposing” in COVID-19 therapy, not only because of their anticoagulant but also possible antiviral effects.

Aims: The aim of the study was to develop new SIRT1 activator compounds, for this aim, we used virtual screening and molecular dynamics methods, which have been important tools for new hit compound searches. Background: Recently, with the progress of computing technology, it has been possible to obtain higher efficiency and lower costs for drug discovery. With in silico research and drug design, there is a reduction in time-consuming and expensive experimental work. An NAD+ dependent histone deacetylase enzyme, Sirtuin 1 (SIRT1), is involved in a variety of human disorders such as type II diabetes, cancer, obesity, and aging. Activation of SIRT1 could be useful for longevity and treating metabolic disorders. Objective: We used computational methods to develop new SIRT1 activator compounds. Methods: Firstly, virtual screening studies on the human SIRT1 enzyme were carried out. We used approximately 150.000 commercially available compounds from the Zinc database, which include FDA-approved drugs. According to virtual screening results, we selected seven potent activators. Then we compared these hit compounds with known activators by using docking methods. One of these hit compounds, acebutolol, is an FDA-approved drug, and was selected for additional studies using molecular dynamics simulations. Results: Seven hit compounds were identified with database screening. Each showed strong interactions with SIRT1, and acebutolol formed H-bonds with the important active site residues, Asn226 and/or Glu230 during the dynamics simulation. Conclusion: Based on our in silico studies, the seven most promising compounds, especially acebutolol, showed promising SIRT1 activator potency. The results may be used to design new selective and more potent SIRT1 activator drugs.

En tr Objective: In this study, pharmacophore models were generated to explain the structure–activity relationships by using the known MMP-9 inhibitors. Material and Method: Pharmacophore models were generated to explain the specification of the structure–activity relationships of common pharmacophoric sites of the known MMP-9 inhibitors. For this study Discovery Studio 3.5 software was used. A set of known MMP-9 inhibitors (NFH, Batimastat, Marimastat, Prinomastat, CGS-27023A, and Ro32-3555) were used for common feature pharmacophore generation method. Selected hypothesis included two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature. Result and Discussion: All of the tested inhibitors except CGS-27023A and Ro32-3555 fitted the selected pharmacophore model perfectly. These two inhibitors didn’t fit the A2 feature. It can be concluded that A1, D1, and H1 features at the given positions could be necessary for the activity. Additionally, we compared the pharmacophore model with NFH and MMP-9 enzyme complex to identify the important interactions. At the given positions of all of the pharmacophoric features, there is an interaction with the protein. This is also supported our pharmacophore hypothesis. As a result, this pharmacophore model could be useful to design new small molecule inhibitors of MMP-9 enzyme. Amaç: Bu çalışmada, yapı-aktivite ilişkilerini açıklamak amacıyla bilinen MMP-9 inhibitörleri üzerinden farmakofor modeller oluşturuldu. Gereç ve Yöntem: Bilinen MMP-9 inhibitörlerinin ortak farmakoforik özellikleri belirlenerek, yapı-aktivite ilişkilerini açıklamak üzere farmakofor modeller oluşturuldu. Bu çalışma için Discovery Studio 3.5 programı kullanıldı. Bilinen MMP-9 inhibitörleri (NFH, Batimastat, Marimastat, Prinomastat, CGS-27023A ve Ro32-3555), ortak farmakofor özelliklerin belirlenmesinde kullanıldı. İki hidrojen bağı alıcısı, bir hidrojen bağı donörü ve bir hidrofobik özellik içeren hipotez seçildi. Sonuç ve Tartışma: CGS-27023A ve Ro32-3555 dışındaki test edilen tüm inhibitörler, seçilen farmakofor modele mükemmel bir şekilde uydu. Bu iki inhibitör A2 özelliğine uymadı. Buna göre, etki için verilen konumlardaki A1, D1 ve H1 özelliklerinin gerekli olabileceği sonucuna varıldı. Ayrıca, önemli etkileşimleri tanımlamak için farmakofor model, NFH ve MMP-9 enzim kompleksi ile karşılaştırıldı. Tüm farmakoforik özelliklerin verilen pozisyonlarda, protein ile bir etkileşim gözlendi. Bu durum farmakofor hipotezimizi de desteklemektedir. Sonuç olarak, bu farmakofor model, MMP-9 enziminin yeni küçük molekül inhibitörlerini tasarlamak için yararlı olabilir.

Human DNA is a very sensitive macromolecule and slight changes in the structure of DNA can have disastrous effects on the organism. When nucleotides are modified, or changed, the resulting DNA sequence can lose its information, if it is part of a gene, or it can become a problem for replication and repair. Human cells can regulate themselves by using a process known as DNA methylation. This methylation is vitally important in cell differentiation and expression of genes. When the methylation is uncontrolled, however, or does not occur in the right place, serious pathophysiological consequences may result. Excess methylation causes changes in the conformation of the DNA double helix. The secondary structure of DNA is highly dependent upon the sequence. Therefore, if the sequence changes slightly the secondary structure can change as well. These slight changes will then cause the doublestranded DNA to be more open and available in some places where large adductions can come in and react with the DNA base pairs. Computer models have been used to simulate a variety of biological processes including protein function and binding, and there is a growing body of evidence that in silico methods can shed light on DNA methylation. Understanding the anomeric effect that contributes to the structural and conformational flexibility of furanose rings through a combination of quantum mechanical and experimental studies is critical for successful molecular dynamic simulations.

Three different organic compounds, 2-phenyl-5-(4-trifloromethyl phenyl sulfonamido) benzoxazole (PTPS), 2-(4-chlorobenzyl)-5-(2,4-dinitrophenylsulfonamido)benzoxazole (CNSB) and 2-(4-fluorobenzyl)-5-(2,4-dinitrophenylsulfonamido)benzoxazole (FBPS), were synthesized. To find their energetically stable conformation, geometry optimization was done using density functional theory with the level B3LYP/cc-pVDZ. Electron distribution of the system was studied using molecular electrostatic potential map. Different intermolecular interactions arising from hyperconjugative effect were investigated using the natural bond orbital (NBO) formalism. Nonlinear optical properties were further studied using first-order hyperpolarizability values. The three compounds may be important in the development of novel inhibitor molecules of Topoisomerase II enzyme, as lead compounds. Light harvesting efficiency of PTPS is 0.9342, which shows that it is having potential applications in the design of new DSSC's.

DNA topoisomerases are proved therapeutic targets of anticancer and antibacterial drugs. Structures of topoisomerase–DNA and inhibitor ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. There are two isoforms of Human Topoisomerase II; α and β. Both of them perform similar functions and their levels differ depending on the replicative activity and type of tissue. Topo IIα is preferentially expressed in proliferating cells. Thus selective Topo IIα inhibitors have been of particular interest in cancer therapy, as they may represent a more targeted approach to highly proliferative cells. In this study, we use structure based virtual screening method with molecules which are commercially available in the ZINC database. Docking studies were performed by Glide module available in Schrödinger software, Ligand filtration was also done to obtain an efficient collection of hit molecules by employing Lipinski “rule of five” and pharmacokinetic properties of the compounds were tested using Qikprop module. From approximately ten thousand compounds from Zinc database it was possible to select 4 top chemical structures with good inhibiting profile for topo II, with suitable ADME/Tox properties, thus comp. 1-4 could be the promising inhibitors of human topo IIα enzyme.

QSAR analysis of thiosemicarbazone derivatives exposing RNR inhibitory activities [1] was performed for 21 compounds. Among these compounds, 13 of them were reported with inhibitory concentration (IC₅₀) in the l M range. The inhibitory concentration of those compounds was converted into -logIC₅₀ before being correlated with the structural features. The quantum chemical calculations have been carried out at the B3LYP at Complete Basis set (CBS) level of theory using Gaussian-09 series of program package. The density functional theory (DFT), Becke’s three parameter exchange function along with the Lee–Yang–Parr correlation function (B3LYP) were considered to calculate the quantum chemical descriptors such as HOMO, LUMO, Energy gap, Hardness, Softness, Chemical potential and Dipole moment of the investigated molecules. The variables make a unique statistically significant contribution (p < 0.05). According to their beta values, electronegativity showed the biggest beta coefficient (–13.225). It has been revealed that variable has a unique contribution to a stronger explanation of dependent variables. Beta values for the electrofugality was slightly lower (8.350), showing least contribution for rest of the elements. Other variables (Energy gap, chemical potential, nucleofugality) measured for this model was statistically significant.