Drug-likeness Parameters Research Articles

Evaluation of anti-inflammatory activity and identification of a monoterpenoidhydroxylactone (-)-loliolide from Tribulus terrestris L.: In-vivo and In-silico Approaches

The present study aimed to determine the anti-inflammatory effects of Tribulusterrestris L (aerial parts) and to identify the anti-inflammatory agents from active extracts and fractions together with in silico prediction of their mechanism of action, pharmacokinetics, and toxicity profile. The anti-inflammatory activity was evaluated for Dichloromethane, methanol, and its fractions (chloroform, ethyl acetate, n-butanol by Carrageenan induced rat paw edema. The phytoconstituents of the anti-inflammatory active fraction (chloroform fraction of methanol extract) was identified using Thermo Scientific TM DFS high-resolution GC-MS. The GC-MS analysis revealed 13 compounds from which (-)-loliolide was the most abundant compound by peak area. It was docked, using Autodock 4.0 onto three Key enzymes involved in the inflammatory cascade (Cyclooxygenase (COX-1 &2) and 5-lipooxygenase (5-LOX)). It displayed binding energies; -6.98 kcal/mole (COX-1) compared to -6.83kcal/mole for standard, -6.64 kcal/mole (COX-2) compared to -6.88 kcal/mole for standard and -5.25 kcal/mole (5-LOX) compared to -6.89 kcal/mole for standard. Toxicity risks, drug likeliness, and pharmacokinetic properties were studied by different online open-source programs. Good binding energy, drug-likeness, and efficient pharmacokinetic parameters of (-)-loliolide suggest it as a good inhibitor, however, further research is needed.

Anti-inflammatory Activity of Pyrazole Analogues Deduced from Bioactive Piperine: Synthesis, In silico, and In vitro Evaluation

Background: Around ten novel pyrazoline and pyrazolidine derivatives were designed and synthesized by the condensation of piperine, hydrazine hydrate, phenylhydrazine, aromatic carboxylic acid, and ethanol. Methods: The synthesized compounds (2, 3, 4a-d, and 5a-d) were characterized by FTIR, 1HNMR, mass spectral, and elemental analysis. Pharmacokinetic, physicochemical, drug-likeness, and medicinal chemistry friendliness parameters were also predicted by in silico methods. Results: Furthermore, compounds were screened for in vitro anti-inflammatory activity by the HRBC membrane stabilization method using diclofenac sodium as the standard drug. The tested compounds showed moderate anti-inflammatory activity compared to the standard drug. The molecular docking studies of significantly active (4d) and least active compounds (5d) were also carried out in the active sites of an arachidonate-12-lipoxygenase target in order to study the putative binding pattern of the study compounds. Conclusion: According to the findings of this study, further lead identification as well as lead optimization techniques will be required in the near future in order to get potent analogues.

Computational design of quinoxaline molecules as VEGFR-2 inhibitors: QSAR modelling, pharmacokinetics, molecular docking, and dynamics simulation studies

Cancer is a deadly condition characterized by accelerated cell proliferation. According to the World Health Organization, global cancer cases are projected to reach 22 million by 2030. Therefore, the relentless search for safer and more effective anticancer drugs remains an imperative direction in the research and progression of drugs targeting cancer. This work utilized a ligand-based approach to designing more effective quinoxaline derivatives for the VEGFR-2 enzyme, an important protein in the pathogenesis of breast cancer. To accomplish this task, a statistically validated QSAR model was built using quinoxaline derivatives. The developed model was used for the virtual screening of the quinoxaline derivatives, from which compound 8 with a high inhibitory capacity (pIC50 = 5.357) was selected as the design template from which five hypothetical molecules with better VEGFR-2 inhibitory capacities ranging from pIC50 = 5.43 to 6.16 were designed. Docking studies were performed with the designed molecules as ligands and the VEGFR-2 active site residues, and they were found to have docking scores ranging from −171.384 to −182.241 kcal/mol, which outperformed the template ligand with a score of −170.579 kcal/mol. MD simulation predicted a stable docked complex and that the ligands did not leave the VEGFR-2 active site over the course of 200ns simulation. The designed quinoxaline molecules exhibit drug-like and desired ADMET parameters, as revealed by the outcomes of drug-likeness and pharmacological profiling. Hence, this research could be significant in unearthing novel breast cancer-targeting molecules.

Benzimidazole-derived carbohydrazones as dual monoamine oxidases and acetylcholinesterase inhibitors: design, synthesis, and evaluation

A series of novel benzimidazole-derived carbohydrazones was designed, synthesized and evaluated for their dual inhibition potential against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) using multitarget-directed ligand approach (MTDL). The investigated compounds have exhibited moderate to excellent in vitro MAOs/AChE inhibitory activity at micromolar to nanomolar concentrations. Compound 12, 2-(1H-Benzo[d]imidazol-1-yl)-N'-[1-(4-hydroxyphenyl) ethylidene]acetohydrazide has emerged as a lead dual MAO-AChE inhibitor by exhibiting superior multi-target activity profile against MAO-A (IC50 = 0.067 ± 0.018 µM), MAO-B (IC50 = 0.029 ± 0.005 µM) and AChE (IC50 = 1.37 ± 0.026 µM). SAR studies suggest that the site A (hydrophobic ring) and site C (semicarbazone linker) modifications attempted on the semicarbazone-based MTDL resulted in a significant enhancement in the MAO-A/B inhibitory potential and a drastic decrease in the AChE inhibitory activity. Further, molecular docking and dynamics simulation experiments disclosed the possible molecular interactions of inhibitors inside the active site of respective enzymes. Also, computational prediction of drug-likeness and ADME parameters of test compounds revealed their drug-like characteristics. Communicated by Ramaswamy H. Sarma

Green Synthesis and Acetylcholinesterase Inhibition of Coumarin-1,2,4-Triazole Hybrids

Abstract: The pursuit of biologically active compounds has led many researchers to synthesize different heterocyclic hybrids with prominent activity. Both coumarin and 1,2,4-triazole are very potent scaffolds whose hybrids have improved biological activities. : This study synthesized twenty-one new coumarin-1,2,4-triazole hybrids in a one-step reaction using choline chloride : urea deep eutectic solvent. The green approach to this synthesis has led to shorter reaction times, higher yields, and purity of final compounds. : The title compounds were characterized and screened for drug-likeness parameters to evaluate their viability as potential drug candidates and for their in vitro acetylcholinesterase inhibitory activity. All tested compounds complied with the drug-likeness rules. However, they exhibited only weak to moderate inhibitory activity against acetylcholinesterase. : Molecular docking analysis revealed that title compounds mostly bind to the peripheral anionic region of the acetylcholinesterase active site, therefore hindering, but not completely obstructing, substrate from entering the enzyme catalytic site.

Studying the Biological Activity of Trans-[Cu (quin)2(EtOH)2] as Potent Antimicrobial Cu(II) Complex through Computational Investigations: DFT, ADMET and Molecular Docking.

Trans-[Cu (quin)2(EtOH)2], a new copper (II) complex, was characterized using a variety of computational techniques to explore its biological role in pharmacological applications. The computational methods included density functional theory (DFT), ADMET and molecular docking. The optimized geometrical parameters revealed that the plane containing the Cu ion and the Quinaldinate ligands was confirmed to be nearly planar. DFT findings suggest that the complex has a stable structure with a moderate band gap of 3.88 eV. Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) analysis revealed a planar surface intramolecular charge transfer from its donor sites, in the center, to its ends instead of the vertical plane. Two electron-rich regions were observed around the oxygen ions in the molecular electrostatic potential (MEP) map, which were expected to be the sites of molecular bonding and interactions with target proteins. Drug-likeness and pharmacokinetics parameters were determined to provide insight into the safety level of the studied compound. The ADMET (absorption, distribution, metabolism, excretion, and toxicity) results showed favorable pharmacological features, as evidenced by a high oral bioavailability and a low risk of toxicity. A molecular docking study was performed by fitting the copper complex into the active sites of target proteins for Bacillus cereus, Staphylococcus aureus, and Escherichia coli bacteria. The title complex had the strongest antifungal effect within the inhibitory zone of B. cereus with a strong binding affinity of -9.83 kcal/mol. Also, maximum activity was exhibited against S.aureus (-6.65 kcal/mol) compared to the other recently reported Cu complexes within the limits of the screened references. Docking studies implicated modest inhibitory activity against E. coli bacteria. The findings highlighted the compound's biological activities and identified it as a possible treatment drug for the bacteria B. cereus and S. aureus.

Novel Functionalized Spiro [Indoline-3,5'-pyrroline]-2,2'dione Derivatives: Synthesis, Characterization, Drug-Likeness, ADME, and Anticancer Potential.

A highly stereo-selective, one-pot, multicomponent method was chosen to synthesize the novel functionalized 1, 3-cycloaddition spirooxindoles (SOXs) (4a-4h). Synthesized SOXs were analyzed for their drug-likeness and ADME parameters and screened for their anticancer activity. Our molecular docking analysis revealed that among all derivatives of SOXs (4a-4h), 4a has a substantial binding affinity (∆G) -6.65, -6.55, -8.73, and -7.27 Kcal/mol with CD-44, EGFR, AKR1D1, and HER-2, respectively. A functional study demonstrated that SOX 4a has a substantial impact on human cancer cell phenotypes exhibiting abnormality in cytoplasmic and nuclear architecture as well as granule formation leading to cell death. SOX 4a treatment robustly induced reactive oxygen species (ROS) generation in cancer cells as observed by enhanced DCFH-DA signals. Overall, our results suggest that SOX (4a) targets CD-44, EGFR, AKR1D1, and HER-2 and induces ROS generation in cancer cells. We conclude that SOX (4a) could be explored as a potential chemotherapeutic molecule against various cancers in appropriate pre-clinical in vitro and in vivo model systems.

A combined spectroscopic and quantum chemical approach to study the molecular interaction between anti-inflammatory drug Hydrocortisone and amino acid l-Phenylalanine

The work presented in the manuscript addresses the molecular interaction of Hydrocortisone with l-Phenylalanine accomplished by density functional theory (B3LYP/6–311 G(d,p)), and spectroscopic approaches such as Raman, SERS, FTIR, and Powder X-ray diffraction (PXRD) methods. Raman and FTIR spectra are collected and compared with the theoretically obtained data and they support each other. Insight into the delocalization scheme of the Hydrocortisone + l-Phenylalanine complex reveals the formation of C=O∙∙∙H intermolecular hydrogen bond. The characterization of the intermolecular interaction by AIM and RGD-NCI analysis demonstrates the presence of both electrostatic and covalent nature. Molecular electrostatic potential mapped and low FMO's gap (-4.99 eV) unveil the reactive nature of the interacting complex. The aqueous solubility assessment of the synthesized complex exhibits almost 2.95 times better solubility as compared to Hydrocortisone. Mulliken atomic charges and thermodynamic parameters are enumerated with B3LYP/6–311 G(d,p) level. The calculated bioactivity score and drug-likeness parameters show good oral bioavailability of the complex. In addition, molecular docking study performed with the target proteins JAK1 (PDB ID: 6DBN) shows binding affinity of −9.43 kcal/mol.

3D-QSAR, homology modelling of influenza hemagglutinin receptor (StrainA/WS/1933), molecular dynamics, DFT, and ADMET studies for newly designed inhibitors

Influenza pandemic cases are related to high morbidity and mortality rates due to the genetic variability of the influenza strains. This necessitated the need for the search and discovery of more potential anti-influenza agents to avert future outbreaks. The 3D-QSAR studies were built through comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results showed CoMFA (Rtrain2 = 0.98, Q2 = 0.58) and CoMSIA (Rtrain2 0.96, Q2 = 0.54) models for reliable activity predictions. Using the worthy information obtained from the field contributors of the 3D-QSAR models and the molecular docking studies of the most active compound 4 (template 4), nine (9) compounds were designed (4a-i) with better potency as compared with a reference drug (arbidol). The dynamic stability of the bound ligand (4d) in the binding site of the modelled protein was further justified through molecular dynamics simulations for up to 100 ns. Moreover, the quantum chemical and drug-likeness parameters of the designed compounds predicted good chemical reactivity and pharmacokinetic profiles respectively. Hence, the outcome of this study recommends the development and bioassay testing of these newly designed compounds through in vitro and in-vivo analysis.

Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19, which was declared a global pandemic in March 2020 by the World Health Organization (WHO). Since SARS-CoV-2 main protease plays an essential role in the virus's life cycle, the design of small drug molecules with lower molecular weight has been a promising development targeting its inhibition. Herein, we evaluated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles against SARS-CoV-2 main protease. We employed molecular dynamics (MD) simulations to elucidate the selected compounds' binding free energy profiles against SARS-CoV-2 and further unveil the residues responsible for the drug-binding properties. Compound 8 exhibited the highest binding free energy of -49.37 ± 0.15 kcal/mol, followed by compound 7 (-39.83 ± 0.19 kcal/mol), while compound 17 showed the lowest binding free energy (-23.54 ± 0.19 kcal/mol). In addition, the absorption, distribution, metabolism, and excretion (ADME) assessment was performed and revealed that only compound 17 met the drug-likeness parameters and exhibited high pharmacokinetics to inhibit CYP1A2, CYP2C19, and CYP2C9 with better absorption potential and blood-brain barrier permeability (BBB) index. The additional intermolecular evaluations suggested compound 8 as a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in compound 7 with an aromatic benzene ring in compound 8 significantly enhanced the drug's ability to bind better at the active site of the SARS-CoV-2 Mpro.

Fragment-Based Drug Design, 2D-QSAR and DFT Calculation: Scaffolds of 1, 2, 4, triazolo [1, 5-a] pyrimidin-7-amines as Potential Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

Background: Plasmodium falciparum dihydroorotate dehydrogenase (PfDODH) is one of the enzymes currently explored in the treatment of malaria. Although there is currently no clinically approved drug targeting PfDODH, many of the compounds in clinical trials have [1, 2, 4,] triazolo [1, 5-a] pyrimidin- 7-amine backbone structure. Objective: This study sought to design new compounds from the fragments of known experimental inhibitors of PfDODH. Methods: Nine experimental compounds retrieved from Drug Bank online were downloaded and broken into fragments using the Schrodinger power shell; the fragments were recombined to generate new ligand structures using the BREED algorithm. The new compounds were docked with PfDODH crystal structure, after which the compounds were filtered with extensive drug-likeness and toxicity parameters. A 2D-QSAR model was built using the multiple linear regression method and externally validated. The electronic properties of the compounds were calculated using the density functional theory method. Results: Structural investigation of the six designed compounds, which had superior binding energies than the standard inhibitors, showed that five of them had [1, 2, 4,] triazolo [1, 5-a] pyrimidin-7-amine moieties and interacted with essential residues at the PfDODH binding site. In addition to their drug-like and pharmacokinetic properties, they also showed minimal toxicities. The externally validated 2D-QSAR model with R2 and Q2 values of 0.6852 and 0.6691 confirmed the inhibitory prowess of these compounds against PfDODH. The DFT calculations showed regions of the molecules prone to electrophilic and nucleophilic attacks. Conclusion: The current study thus provides insight into the development of a new set of potent PfDODH inhibitors.

Histidinal-Based Potent Antimalarial Agents.

Herein we report the synthesis and evaluation of peptide-histidinal conjugated drug scaffolds, which have the potential to target the hemoglobin-degrading proteases falcipain-2/3 from the human malaria parasite. Scaffolds with various substitutions were tested for antimalarial activity, and compounds 8 g, 8 h, and 15 exhibited EC50 values of ∼0.018 μM, ∼0.069 μM, and ∼0.02 μM, respectively. Structure-based docking studies on falcipain-2/3 proteases (PDB:2GHU and PDB:3BWK) revealed that compounds 8 g, 8 h, and 15 interact strongly with binding sites of falcipain-2/3 in a substrate-like manner. In silico ADME studies revealed that the molecules of interest showed no or minimal violations of drug-likeness parameters. Further, phenotypic assays revealed that compound 8 g and its biotinylated version inhibit hemoglobin degradation in the parasite food vacuole. The identification of falcipain-2/3 targeting potent inhibitors of the malaria parasite can serve as a starting point for the development of lead compounds as future antimalarial drug candidates.

Seleno-indoles trigger reactive oxygen species and mitochondrial dysfunction in Leishmania amazonensis

Leishmaniasis is an endemic disease caused by obligate intracellular protozoa of the genus Leishmania prevalent in the Americas, Africa, and Asia. Therapeutic options are limited for this disease and serious drawbacks are related to the administration of these drugs. Moreover, currently there is no vaccine against leishmaniasis, reinforcing the need to develop new therapeutic options. In the last decade several organoselenium and indolic compounds were reported for their ability to exert activity against different species of Leishmania, posing as promising scaffolds for the development of new drug candidates. In this study, we designed and synthesized a series of thirteen seleno-indoles and investigated their activity against Leishmania amazonensis promastigotes and amastigotes. The most promising seleno-indoles 2a, 2c, 2f, 2g and 3a show good activity against L. amazonensis promastigote and amastigote forms, presenting low toxicity to mammalian cells and good in silico ADMETox and druglikeness parameters, supporting the hypothesis as they being a promising scaffold for further investigation. Mechanistic studies revealed that seleno-indoles 2a, 2c, 2f, 2g and 3a can act interfering with membrane integrity, 2f, 2g and 3a also lead to mitochondrial dysfunction and ROS production, while compound 2a caused mitochondrial depolarization without alteration in ROS generation.

Nigelladine A among Selected Compounds from Nigella sativa Exhibits Propitious Interaction with Omicron Variant of SARS-CoV-2: An In Silico Study.

COVID-19 has been a threat to the entire world for more than two years since its outbreak in December 2019 in Wuhan city of China. SARS-CoV-2, the causative agent, had been reported to mutate over time exposing new variants. To date, no impeccable cure for the disease has been unveiled. This study outlines an extensive in silico approach to scrutinize certain phytochemical compounds of Nigella sativa (mainly the black cumin seeds) targeting the spike protein and the main protease (Mpro) enzyme of the Omicron variant of SARS-CoV-2. The objective of this study is to investigate the extracted compounds with a view to developing a potential inhibitor against the concerned SARS-CoV-2 variant. The investigation contemplates drug-likeness analysis, molecular docking study, ADME and toxicity prediction, and molecular dynamics simulation which have been executed to elucidate different phytochemical and pharmacological properties of the tested compounds. Based on drug-likeness parameters, a total of 96 phytochemical compounds from N. sativa have been screened in the study. Interestingly, Nigelladine A among the compounds exhibited the highest docking score with both the targets with the same binding affinity which is -7.8 kcal/mol. However, dithymoquinone, kaempferol, Nigelladine B, Nigellidine, and Nigellidine sulphate showed mentionable docking scores. Molecular dynamics up to 100 nanoseconds were simulated under GROMOS96 43a1 force field for the protein-ligand complexes exhibiting the top-docking score. The root mean square deviations (RMSD), root mean square fluctuations (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), and the number of hydrogen bonds have been evaluated during the simulation. From the findings, the present study suggests that Nigelladine A showed the most promising results among the selected molecules. This framework, however, interprets only a group of computational analyses on selected phytochemicals. Further investigations are required to validate the compound as a promising drug against the selected variant of SARS-CoV-2.

Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study.

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining binding within the substrate-binding cavity of Mpro. We further performed comparative analyses of the reference and effective complexes in terms of dynamics, thermodynamics, binding free energy (BFE), and interaction energies and modes. The results reveal that, when compared to the inter-molecular electrostatic forces/interactions, the inter-molecular van der Waals (vdW) forces/interactions are far more important in maintaining the association and determining the high affinity. Given the un-favorable effects of the inter-molecular electrostatic interactions-association destabilization by the competitive hydrogen bond (HB) interactions and the reduced binding affinity arising from the un-compensable increase in the electrostatic desolvation penalty-we suggest that enhancing the inter-molecular vdW interactions while avoiding introducing the deeply buried HBs may be a promising strategy in future inhibitor optimization.

Ginger ring compounds as an inhibitor of spike binding protein of alpha, beta, gamma and delta variants of SARS-CoV-2: An in-silico study.

The available drugs against coronavirus disease 2019 (COVOD-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are limited. This study aimed to identify ginger-derived compounds that might neutralize SARS-CoV-2 and prevent its entry into host cells. Ring compounds of ginger were screened against spike (S) protein of alpha, beta, gamma, and delta variants of SARS-CoV-2. The S protein FASTA sequence was retrieved from Global Initiative on Sharing Avian Influenza Data (GISAID) and converted into ".pdb" format using Open Babel tool. A total of 306 compounds were identified from ginger through food and phyto-databases. Out of those, 38 ring compounds were subjected to docking analysis using CB Dock online program which implies AutoDock Vina for docking. The Vina score was recorded, which reflects the affinity between ligands and receptors. Further, the Protein Ligand Interaction Profiler (PLIP) program for detecting the type of interaction between ligand-receptor was used. SwissADME was used to compute druglikeness parameters and pharmacokinetics characteristics. Furthermore, energy minimization was performed by using Swiss PDB Viewer (SPDBV) and energy after minimization was recorded. Molecular dynamic simulation was performed to find the stability of protein-ligand complex and root-mean- square deviation (RMSD) as well as root-mean-square fluctuation (RMSF) were calculated and recorded by using myPresto v5.0. Our study suggested that 17 out of 38 ring compounds of ginger were very likely to bind the S protein of SARS-CoV-2. Seventeen out of 38 ring compounds showed high affinity of binding with S protein of alpha, beta, gamma, and delta variants of SARS-CoV-2. The RMSD showed the stability of the complex was parallel to the S protein monomer. These computer-aided predictions give an insight into the possibility of ginger ring compounds as potential anti-SARS-CoV-2 worthy of in vitro investigations.

Anticholinesterase Agents For Alzheimer's Disease Treatment: An Updated Overview.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that compromises the cognitive system and causes dementia. In general, AD affects people over 65 years old, which implies a social impact if we consider future projections due to the increase in life expectancy. The drugs currently marketed only slow the progression of the disease. In this sense, the search for new drugs is a relevant topic in medicinal chemistry. The therapeutic strategy adopted herein is the cholinergic hypothesis, for which acetylcholinesterase enzyme (AChE) inhibitors constitute the main treatment for the disease. This review compiles research in synthetic and natural compounds with AChE inhibitory function. Data were collected based on investigations of AChE inhibitors in the last 5 years of the 2010 decade. Synthetic and natural compounds were investigated, for which Ligand Based Drug Design (LBDD) and Structure Based Drug Design (SBDD) strategies were performed to better understand the structure-activity relationship of promising therapeutic agents. Prediction of physicochemical and pharmacokinetic properties used to calculate the bioavailability radar, lipophilicity, drug-likeness, and pharmacokinetics parameters (SwissADME) indicated that most active compounds are associated with the following characteristics: molecular weight above 377 g/mol; molar refractivity over 114; fraction Csp3 below 0.39 and TPSA above 43 Å2. The most active compounds had a lipophilicity parameter in the range between 2.5 and 4.52, a predominating lipophilic character. Atoms and bonds/interactions relevant for drug development were also investigated and the data pointed out the following tendencies: number of heavy atoms between 16 and 41; number of aromatic heavy atoms between 6 and 22; number of rotatable bonds between 1 and 14; number of H-bond acceptors between 1 and 11; number of H-bond donors below 7. Molecular docking studies indicated that all compounds had higher Goldscores than the drugs used as a positive control, indicating a stronger interaction with the enzyme. The selected compounds represent a potential for new anticholinesterase drugs and may be good starting-point for the development of new candidates. Also, design rules can be extracted from our analysis.

In Silico Molecular Docking Study for Prediction of Binding Affinities to Penicillin Binding Proteins and β-Lactamases of Amino Acids-Cephalexin conjugates

Cephalexin is a first generation cephalosporin with high antibacterial activity against a number of microbes. Cephalexin is highly sensitive and could be hydrolyzed by almost all of β-lactamases. An in silico prediction and evaluation study is performed to find a possibility of bringing new life to cephalexin, and other cephalosporins that are susceptible to hydrolysis by lactamases. This approach includes an introduction of an amino acid moiety into cephalexin through an amide bond with its primary amine group. This amino acid moiety is expected to provide steric hindrance and protecting the β-lactam ring from being hydrolyzed. In silico study included measurement of binding affinity to penicillin binding proteins (PBPs) and D-alanyl-D-alanine carboxypeptidases and to β-lactamases. Drug likeness and Molinspiration calculations were recorded to find a reliable correlation with better activity and stability against β-lactamases. The newly suggested conjugates that recorded the best score of binding affinity on PBPs are L-Phe-Cephalexin, L-Arg-Cephalexin, L-Tyr-Cephalexin and L-Thr-Cephalexin. Two of these conjugates, namely, L-Arg-Cephalexin and L-Tyr-Cephalexin recorded high binding affinity scores on D-alanyl-D-alanine carboxypeptidases. Moreover, the predicted stability of L-Arg-Cephalexin and L-Tyr-Cephalexin conjugates against β-lactamases was recorded. Drug-Likeness parameters have shown that L-Cys-Cephalexin, L-Lys-Cephalexin and L-Arg-Cephalexin conjugates were the best compounds recording the highest binding affinity. In conclusion, the amino acid-linked cephalexin conjugates were found to possess high binding affinity to PBPs, D-alanyl-D-alanine carboxypeptidases and β-lactamases, which may encourage the synthesis and intensive evaluation.

Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease

Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that has a profound impact on memory, reasoning, learning, and organizational abilities. Acetylcholinesterase is one of the well-established targets for managing this disease. However, the existing acetylcholinesterase inhibitors are limited in many ways. Hence, in this study, we aimed to identify potential new drugs that can be repurposed to treat AD. For this purpose, an in silico screening of drug molecules that are structural analogues of the three FDA-approved acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine was performed, and 308 analogous compounds were recognized. To find the best possible drug repurposing candidates among them, an extremely rigorous filtering pipeline consisting of several drug-likeness parameters such as Lipinski, Ghose, Veber, Egan, Muegge, lead-likeness, and blood-brain barrier permeability was implemented. Finally, only 61 remained out of the 308 compounds. These 61 compounds then underwent molecular docking against the acetylcholinesterase receptor. Six compounds exhibited a higher binding affinity for the receptor compared to the FDA-approved drugs which were used as controls. Except for one compound that formed unfavorable molecular interactions, the rest were then subjected to sophisticated molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculation in order to evaluate their binding properties under a simulated physiological environment. Based on all the analyses, we are suggesting Dexketoprofen, a nonsteroidal anti-inflammatory drug as the most promising candidate for repurposing against AD. Our findings will pave the way for narrowing down the list of candidates to be tested in vitro and in vivo in further studies.

Vibrational spectroscopic, electronic influences, reactivity analysis and molecular docking studies of 2-Fluoro-4-iodo-5-methylpyridine

Geometrical optimization along with spectroscopic survey and electronic scrutiny of 2-Fluoro-4-iodo-5-methylpyridine were carried out by exercising Density-functional theory. The intramolecular hydrogen bonding interaction of the caption compound was investigated by means of the Natural Bond Orbital analysis. The Highest Occupied Molecular Orbital & Lowest Unoccupied Molecular Orbital energies, Mulliken charges, and Non-Linear Optic properties were procured in dissimilar liquids to analyze the solvent influence. The Theoretic Ultraviolet-visible spectrum of the investigation compound has been accomplished using Time-dependent density-functional theory in different solvents chosen. A Molecular Electrostatic Potential study has been achieved and conferred in terms of color distribution shows the reactive regions for protein interactions. Additionally, Electron localization function, Localized orbital locator and Reduced density gradient analysis of the caption compound were also studied. Furthermore, to reveal the biological importance of the caption compound, drug-likeness parameters have been computed and docking of the heading compound into the energetic site of the target proteins were performed to confirm that this compound has drug behavior.