Journal of Computational Biophysics and Chemistry

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a novel coronavirus, is a member of the Coronoviridae family that has spread worldwide. Developing efficacious therapeutics for the treatment of SARS-CoV-2 is of high priority. Therefore, in this study, the chemical constituents obtained from Tinospora cordifolia are investigated for their in-silico interaction with protein targets crucial for SARSCoV-2 infection and cytokine storm. The five important targets chosen for SARSCoV-2 were the main protease (Mpro), Spike receptor binding domain (Spike-RBD), RNA-dependent RNA polymerase (RdRp or Nsp12), nonstructural protein 15 (Nsp15) of SARS-CoV-2 and the host angiotensin converting enzyme-2 (ACE-2) spike-RBD binding domain and cytokine receptors TNF-$\alpha$ (Tumor Necrosis Factor-$\alpha$) and IL-6 (Interleukine-6). This was accomplished using Maestro 12.4 (Schrodinger Suite) to obtain docking scores. Also, the absorption, distribution, metabolism, elimination, and toxicity parameters (ADMET) were determined using Maestro QikProp modules. The results of computational study revealed that four constituents Cordifolioside-A, Palmatoside-E, Tinocordioside and Tinosporaside significantly antagonize the five targets of SARS-CoV-2 by binding in the binding pocket with docking score ranging from −9.664 to −6.488 kcal/mol and shows drug-like property and also effectively inhibit cytokine storm by antagonizing the TNF-$\alpha$ and IL-6 receptors. Promising drug-like properties, excellent docking scores, and binding pose against each target makes the screened compounds as possible lead candidate which can be further evaluated in future studies to assess their in vitro and in vivo efficacy against SARS-CoV-2. The structure of these compounds can be used further for optimization and design of drugs against COVID-19.

Both sulforaphane (SF) and cisplatin (CP) are well-known anticancer drugs and in some cases, they are used simultaneously for the treatment of a wide range of cancers. SF is the main component of cruciferous vegetables such as broccoli. CP is a four-coordinated complex of platinum, Pt(NH₃)Cl₂. The interaction of SF with CP is important since a ligand of this inorganic complex might be replaced by SF. In this work, the complexation of SF with CP has been studied theoretically using an accurate high-level ab initio method, together with a reliable method of density functional theory method. Calculations are extended to solution phase by means of solvation model density. Different functional groups of SF are investigated so that the most active site of SF in reaction with CP is determined from both thermodynamics and kinetics points of view. Derivatives of SF have been also studied in order to improve their solbilities in aqueous solution. The results of this work show that SF can form a stable complex with CP and interactions of these two compounds should be considered.

Fungal infection of invasive nature is an alarming threat globally and a leading cause of human morbidity and mortality as they are opportunistic in nature. Rising resistance to current clinically approved marketed products for fungal infections is a major concern for humans. Dihydrofolate Reductase (DHFRase) is an essential enzyme in folate metabolic pathway responsible for DNA synthesis and is ubiquitous to all organisms, and also acts as a key target for developing antifungal drugs. In this study, potential mutant DHFRase inhibitors were screened with the help of hierarchical mode of docking of virtual library of antifungal compounds and molecular dynamic (MD) simulation. The identification of best hits was done by using the docking, binding energy prediction and further, which was supported by their predicted pharmacokinetics. MD simulation of the human DHFRase enzyme with the reference lead compound i.e. PY957 and most promising hit found i.e. ChemDiv-C390-0455 and to validate the stability of enzyme-ligand complex in best 07 retrieved hit as a potential mutant DHFRase inhibitor. The key residues Glh30, Phe34, Phe64, Phe31 of the binding pocket acknowledged as essential were found to be matching with the key interactions of the selected hit. Computed root mean square deviation (RMSD) and root mean square fluctuation (RMSF) in MD simulation of complex of DHFRase enzyme with PY957 and ChemDiv-C390-0455 were read less than 2.25Å during 100 nanoseconds simulation for both complex.

Histone deacetylase (HDAC) enzymes modify the histone by removing the acetyl group from the lysine residues, known as histone deacetylation. HDACs have been involved in altering gene expressions, resulting in cancer cells in the body. This study focuses on HDAC inhibitors’ impact on histone deacetylase-like protein (HDLP) stability through computational techniques. Molecular dynamics (MD) analyses were used to examine the atomic-level description of drug binding sites and how the HDAC inhibitors change the HDLP enzyme environment. In this study, two hydroxamic acid-derived inhibitors, such as $m$-Carboxycinnamic acid bis-hydroxamide (CBHA) and scriptaid (GCK1026), were selected to examine the inhibition ability in terms with suberanilohydroxamic acid (SAHA) as a reference drug. The crystal structure of the HDLP was downloaded from the Protein Data Bank. The structures of inhibitors were optimized using the G09W package. Docking studies were done by AutoDock-Vina, and the resultant complex was used to initiate MD studies. The trajectories obtained from MD simulation were used to perform the structural analysis. Root-mean-square deviation (RMSD), radius of gyration, hydrogen bond, binding free energy and interaction energy studies revealed that the stability of HDLP-SAHA and HDLP-CBHA is higher than the free HDLP enzyme. The HDLP-CBHA complex shows an increased number of hydrogen bonds (5), high MM-PBSA binding free energy ($-328.1\pm 3.4$kJ/mol), high interaction energy ($-227.13\pm 1.7$kJ/mol), and an increased number of alpha-helical amino acids (130) compared with HDLP-SAHA. It concluded that the CBHA has the relatively same potential as SAHA to inhibit the HDLP. Consequently, the use of CBHA in clinical application is recommended through this in-silico method.

In this paper, we have discussed for the first time a detailed electronic absorption study of the mono-azo dye Direct Yellow 27 [C${}_{25}$H${}_{20}$N₄Na₂O₉S₃] (DY-27) with five different homogeneous media by applying experimental and theoretical techniques along with some new characteristics of DY-27 in the field of solar cells as well as antiviral activities. A clear absorption band in the UV-visible region was observed, although the absorption maxima lie in the visible region. The electronic absorption transitions observed in our study were fully spin and symmetry allowed transitions with $\pi$–${\pi }^{\ast }$ character. Time-dependent density functional theory (TD-DFT) analysis has been done for understanding the electronic and the charge transfer performance. Moreover, the impacts of polar protic and polar aprotic solvents in the structural variation of DY-27 have been reported here. Further, applications of the dye in the field of solar cell, as well as antiviral activity, were performed using molecular modeling approaches. The dye exhibited a D–$\pi$–A–A structure with a high light-harvesting efficiency (LHE) and good injection efficiency acts as an effective dye sensitized solar cell (DSSC). Molecular docking studies of the dye DY-27 performed with M-protease of the different corona viruses, MERS, SARS-CoV-1 and SARS-CoV-2 indicated comparable binding energies with the controlled inhibitors and best interactions are observed for the SARS-CoV-1.

Hepatitis C Virus (HCV), affecting millions of people worldwide, is the leading cause of liver disorder, cirrhosis, and hepatocellular carcinoma. HCV is genetically diverse having seven genotypes and several subtypes that are predominant in different regions of the globe. The HCV NS3/4A protease is a major therapeutic target for HCV with various direct acting FDA approved antivirals, and several in clinical development. However, available protease inhibitors (PIs) have lower potency against HCV genotype 3, prevalent in South Asia. Lack of structural data limited our ability to recognize loss of inhibitory potential of PIs. In this study, we attempted to get structural insight of protease GT3 by modeling techniques. The incumbent computational tools were utilized to understand and explore interactions of HCV GT3 receptor with the potential inhibitors after virtual screening of in-house synthesized compound library. The molecular dynamics and pharmacological studies revealed compound Li_PIS_19 exhibiting the favorable binding and better pharmacokinetics properties that may be considered as the most promising compound against HCV GT3 protease.

The self-assembly of human insulin (HI) plays a crucial role in regulating amyloid fibrils. Therefore, it is a significant problem for the medical management of diabetes therapy and these findings have led us to investigate the amyloid formation and its inhibition. Few potential inhibitors have been identified to inhibit amyloid fibrils. Rosmarinic acid (RA) is one of the things that inhibits amyloid formation completely by increasing the resistivity of the amyloidogenic insulin (dimer) protein to thermal unfolding. Here, we choose different tested derivative compounds for designing amyloid inhibitors by substituting various functional groups of RA. These derivative compounds were subjected to in silico studies to determine the best drug candidates. In comparison to RA, 14 molecules have higher binding affinity and interactions with the target receptor. After frontier molecular orbitals study, ADME and toxicity analysis, the eight best compounds may act as the best inhibitors. The stability of the docked complexes was visualized by molecular dynamics (MD) simulations. This finding opens a new proposal to explore future studies with these best compounds to increase the thermal stability of the insulin dimers.

The antioxidative activity and free radical scavenging potency of usnic acid towards eight selected free radical species are examined. The thermodynamic parameters in the absence of harmful free radicals are used to predict the most favorable mechanism of antioxidative action. The reaction enthalpies are used to define the most probable mechanism of free radical scavenging in the presence of free radical species. The obtained results indicate that the favorable mechanism of antiradical action is dependent both on the polarity of solvents and the nature of free radical species. From the achieved results, it is clear that Sequential Proton Loss Electron Transfer (SPLET) is the most probable for antioxidative action in water and methanol, while competition between SPLET and Hydrogen Atom Transfer (HAT) is presented in benzene. The free radical scavenging of eight free radical species under investigation is possible, and the most believable mechanism of action is SPLET, in all three investigated solvents. Since usnic acid exhibits significant radical scavenging activity that affects the maintenance of redox hemostasis, its inhibitory potency toward COVID-19 targeted proteins molecular docking study is performed. The obtained results indicate that usnic acid has the potential to inhibit the functional proteins of SARS-CoV-2.