Journal of Computational Biophysics and Chemistry

Antibacterial treatment has grown difficult due to the increasing growth in bacterial infections, as well as their tolerance to most first-line antibiotics. This is a severe danger to the world’s human health in the 21st century, necessitating further research to identify drugs with improved antibacterial effects and broad-spectrum functions. This study aimed to discover anti-bacterial agents through the molecular docking and in silico approach. Most responsive thirty (32) compounds on UPLC-Q-TOF/MS analysis were selected from our previous report to get the hit compound(s) against inhibition of cell wall synthesis, inhibition of protein synthesis, interference with nucleic acid synthesis, inhibition of a metabolic pathway, inhibition of membrane function and inhibition of adenosine triphosphate (ATP) synthase. From the molecular docking results, we afforded six compounds for cell wall synthesis protein, four compounds for protein synthesis protein, five for nucleic acid synthesis protein, three for metabolic pathway protein, four for membrane function protein and three for ATP synthase protein which eventually undergoes the pharmacokinetic and drug-likeness properties to obtain lead compound(s). Finally, we discovered that compounds Turpinionosides B, Polydatin, Ledebouriellol, and Pterodontoside A have the strongest binding interactions with cell wall synthesis, inhibition of protein synthesis and inhibition of metabolic pathway synthesis, interference with nucleic acid synthesis and inhibition of ATP synthase, inhibition of membrane function proteins, respectively. These compounds have the potential to become an anti-bacterial therapeutic candidate due to their promising pharmacological properties.

Upregulation of MAPK pathway receptors has been majorly reported for the accumulation of tumor cells in non-small cell lung cancer (NSCLC) patients. Several scientific endeavors were committed to developing checkpoint inhibitors for MAPK intermediates. However, poor toxicity profiling and over-expression of other kinases diminish the treatment outcomes. Recently, dual-action drugs are developed to overcome the ineptness and drug resistance that typically occur when the usage of individual checkpoint inhibitors. Therefore, we screened 1574 natural compounds from the NPACT database using high-end computational tools against these attractive kinase targets (RAF and MEK). Initially, Glide docking and prime-MM/GBSA analysis yielded a total of seven hit compounds that showed better binding potency on both targets. The van der Waals interaction energy highly favors the binding of the compound with respective target receptors. Later, we used dynamics ensembles to examine the essential and stable interactions in the complex structures through 16 different MD simulations (50ns) cumulatively in both RAF and MEK systems. These extensive MD analyses resulted in two lead compounds such as NPACT00282 and NPACT01075 having the potential to make a stable complex with RAF and MEK receptors. Notably, the interaction of compounds with CYS532 and TYR125 in RAF and MEK, respectively, might play a crucial role in the compound’s binding process. Furthermore, these lead compounds exhibited good pharmacokinetic/dynamic characteristics. Collectively, we believe that these lead compounds are able to provide better therapeutic options and thus overcome the shortcomings in lung cancer treatment.

ADP-ribosyltransferase 2 (ARTD2) acts as a DNA break sensor and catalyzes the synthesis of polymers of ADP-ribose covalently attached to acceptor proteins at DNA damage sites. Its catalytic domain (CAT) contains a variety of aromatic amino aid residues that can form multiple $\pi$-stacking interactions with substrates and inhibitors. Here, we systematically examined the intermolecular interaction of ARTD2 CAT domain with its cognate small-molecule inhibitors using hybrid quantum mechanics calculations and found that $\pi$-stacking plays a critical role in the ARTD2-inhibitor recognition and association, where a number of ARTD2 inner aromatic residues contribute significantly to the inhibitor binding. A further molecular design of peptidic ligands was performed based on the structural basis and energetic property of the $\pi$-stacking system involved in ARTD2/inhibitor interaction. These peptidic ligands are all $\pi$ electron-rich and composed of diverse unnatural aromatic amino acids. Interaction analysis revealed that the relative contribution of the $\pi$-stacking system to ARTD2 affinity was improved from small-molecule inhibitors to peptidic ligands, although their total binding energies are roughly comparable. Subsequently, the computational findings were substantiated with biochemical assays, where several representative peptidic ligands were determined to have satisfactory inhibitory profiles against ARTD2 with biological activity at the nanomolar level. Structural analysis of ARTD2/peptidic ligand complexes observed a multiple $\pi$-stacking networks at the computationally modeled complex interface of ARTD2 CAT domain with designed peptidic ligands, which can work with other nonbonded interactions such as hydrogen bonds and hydrophobic contacts to confer stability and selectivity for the complex recognition and association.

Amyloid $\beta$ (A$\beta$) peptide monomers polymerize to form insoluble amyloid fibril aggregates and accumulate as senile plaques which eventually leads to cognitive impairment. Modulating abnormal amyloid aggregation can be considered a therapeutic target for Alzheimer’s disease. Recent studies support that Curcumin interferes with larger protein aggregate formation by destabilizing the salt bridge (Asp 23-Lys 28) of A$\beta$ protein. The chemical library of curcumin derivative with pyrazole, isoxazole, and isothiazole showed considerable binding affinity comparable to that of curcumin. In silico docking studies of the library of the compound, revealed strong binding affinity with A$\beta$ protein and $\beta$-secretase enzyme (BACE1). De novo ligand design coupled with manual pharmacophore mapping of our best-fitting lead revealed another ligand having a potential binding affinity with both A$\beta$ protein and BACE-1. Both the compounds passed Lipinski’s Rule of Five, in silico toxicity testing by admetSAR, and pharmacophore overlaps with Verubecestat, a compound under clinical trial against Alzheimer’s disease. MD dynamic simulation study revealed the stability of protein after it binds to our ligand. Secondary structure determination was also done to observe the changes in $\alpha$ and $\beta$ sheets of the protein with and without ligand binding. Ligand-based drug design was also carried out via pharmacophore mapping and searching the molecules via zinc database.

SARS-CoV-2, which causes COVID-19 disease, has proven to be a disastrous pandemic due to its contagious nature. This study has been planned to theoretically explore some antidotes against this virus from natural compounds. A total of 150 compounds from the shogaol class and shogaol derivatives (SDs) have been screened whereas 50 among those, which obeyed Lipinski’s Rule of Five (Ro5), have further been investigated using molecular docking techniques. Furthermore, reference antiviral drug chloroquine (ChQ) and Co-Crystallized inhibitor have also been studied against M^pro of SARS-CoV-2 for comparing the potential of our docked ligands. Surprisingly, 78% of our docked ligands have shown binding energies and inhibition constants lower than ChQ and all ligands showed these values lower than an inhibitor. We further visualized the nature of intermolecular interactions for the best docked six ligands, which have shown higher binding affinities. We have also assessed ADMET properties for three ligands that displayed visually the best intermolecular interactions. Quantum analysis of three selected ligands L4, L5, and L9 has proved their reactivity and kinetic stability. Moreover, molecular dynamic simulations over 60ns have been run for free M^pro and its selected three ligand-protein complexes for evaluating conformational stability and residual flexibility of docked complexes. Furthermore, 100ns the MD simulations have been performed for two ligand complexes L4, L5 (with negative binding free energy), and inhibitor. Available parameters suggest stable complexes for our ligands and could be active drugs against SARS-CoV-2 in near future.

According to the limited medications for COVID-19, natural products gained increasing attention. Scientific indications revealed the effect of biflavonoids (BFs) against respiratory syndrome viruses. The functional importance of 3-chymotrypsin-like protease (3CLpro) in forming viral RNA raises its potential to be targeted in SARS-CoV2. This study is devoted to the computational analysis of privileged BFs within the SARS-CoV2 3CLpro active site. Docking and molecular dynamics (MD) simulations were collectively used to explore the most probable binding modes and stable ligand–enzyme chemical interactions. Despite the structural resemblance, a wide range of binding affinities was retrieved for BFs ($\mathrm{\Delta }{G}_b-7.11-12.66$kcal/mol). Garciniaflavone C ($\mathrm{\Delta }{G}_b-12.66$kcal/mol), 7,7${}^{\prime \prime }$, 4${}^{\prime \prime \prime }$-tri-O-methylagathisflavone ($\mathrm{\Delta }{G}_b-12.16$kcal/mol) and 8,8${}^{\prime \prime }$-biapigenil ($\mathrm{\Delta }{G}_b-12.08$kcal/mol) were top enzyme binders. The stability of acquired complexes was analyzed through 50-ns all-atom MD simulations. Garciniaflavone C, 7,7${}^{\prime \prime }$, 4${}^{\prime \prime \prime }$-tri-O-methylagathisflavone and 8,8${}^{\prime \prime }$-biapigenil showed 29%, 22% and 23% persevered binding residues, respectively. SARS-CoV2-garciniaflavone C complex was mediated by several nonpolar interactions. MD simulations assigned H-bond interaction between the catalytic dyad residue Cys145 and garciniaflavone C. 7,7${}^{\prime \prime }$, 4${}^{\prime \prime \prime }$-tri-O-methylagathisflavone participated in a $\pi$-cation interaction to His41. Solvent accessible surface area distribution indicated the sufficiency of MD simulation time (50ns) to screen equilibrated complex systems. Although a detailed pharmacological mechanism is to be elucidated, our findings indicated superior binding stability of 7,7${}^{\prime \prime }$, 4${}^{\prime \prime \prime }$-tri-O-methylagathisflavone within SARS-CoV2 active site. While the biological function of the majority of BF derivatives remains to be elucidated, results of the current study revealed key structural features and potentials of privileged BFs for further structure-guided optimization toward potent SARS-CoV2 3CLpro inhibitors.

Recently, anti-cancer targeting drugs are directed against specific molecules and signaling pathways. These targeting agents have reasonable specificity, efficacy and less side effects. Tyrosine kinases, which play an essential role in growth factor signaling regulation, are significant targets in this type of therapy. Synthesized numerous tyrosine-kinase inhibitors (TKIs), such as substituted indolin-2-ones, are effective as anti-tumor and anti-leukemia agents. In this study, a series of novel substituted indolin-2-ones were studied as kinase inhibitor analogs through quantitative structure–activity relationship (QSAR) analysis. Two chemometrics methods, such as multiple linear regression (MLR) and partial least squares combined with genetic algorithm for variable selection (GA-PLS), were employed to establish relationships between structural characteristics and kinase inhibitory activity of used oxindole analogs. The GA-PLS was developed as the best predictor and validated QSAR model. The data set compounds were also studied by molecular docking to investigate their binding mechanism in the active site of tyrosine kinase enzyme. According to the information obtained from QSAR models and molecular docking analysis, 40 new potent lead compounds with novel structural features were introduced. Molecular docking, drug-likeness rules, ADMET analysis, bioavailability, toxicity prediction and target identification were carried out on the newly designed oxindoles to elucidate fundamental structural properties that affect their inhibitory activity.

Phthalocyanines (Pcs) are an important group of substances with interesting chemical and physical properties with many different application areas. The use of Pc compounds in photodynamic therapy (PDT), especially in the treatment of cancer, has gained great importance in recent years. In this study, the spectral and electronic properties of new PDT active anticancer non-peripheral tetrakis [2-mercaptoquinoline]phthalocyanine and metal complexes were examined by using Density Functional Theory (DFT). Their properties were computed in DMSO and water phases. The UV absorption spectrum study results show that the main transition responsible for the Q band of the molecular spectrum is from $\pi$ to ${\pi }^{\ast }$. The presence of the heavier atom in the Pc cavity has the effect of enhancing the fluorescence quantum yield. In addition, photochemical singlet oxygen production of newly synthesized phthalocyanine and metal complexes was also investigated. The calculated spectral (UV, IR, NMR) and singlet oxygen yield results were compared with the experimental ones and they were in good agreement.