Identification of Anticancer and Anti-inflammatory Drugs from Drug-target Interaction Descriptors by Machine Learning..

Background: Drug repositioning is an important subject in drug-disease research. In the past, most studies simply used drug descriptors as the feature vector to classify drugs or targets, or used qualitative data about drug-target or drug-disease to predict drug-target interactions. These data provide limited information for drug repositioning. Objective: Considering both drugs and targets and constructing quantitative drug-target interaction descriptors as a method of drug characteristics are of great significance to the study of drug repositioning. Methods: Taking anticancer and anti-inflammatory drugs as research objects, the interaction sites between drugs and targets were determined by molecular docking. Sixty-seven drug-target interaction descriptors were calculated to describe the drug-target interactions, and 22 important descriptors were screened for drug classification by SVM, LightGBM and MLP. Results: The accuracy of SVM, LightGBM and MLP reached 93.29%, 92.68% and 94.51%, their Matthews correlation coefficients reached 0.852, 0.840 and 0.882, and their areas under the ROC curve reached 0.977, 0.969 and 0.968, respectively. Conclusion: Using drug-target interaction descriptors to build machine learning models can obtain better results for drug classification. Number of atom pairs, force field, hydrophobic interactions and bSASA are the four types of key features for the classification of anticancer and anti-inflammatory drugs.

Novel 1,2-thiazine-pyridine hybrid: Design, synthesis, antioxidant activity and molecular docking study

Background & objectives: 1,2-thiazine and pyridine heterocycles drew much attention due to their biological activities including antioxidant activity. Based upon fragment based drug design, novel pyrido[1,2]thiazines 9a-c, thiazolidinopyrido[1,2]thiazines 10a-c and azetidinopyrido[1,2]thiazines 11a-c were designed and prepared. Methods: These novel derivatives 9a-c, 10a-c and 11a-c were subjected to screening for their antioxidant activity via various assays as DPPH radical scavenging potential, reducing power assay and metal chelating potential. Results: All the assayed derivatives exhibited excellent antioxidant potential and the tested compounds 9a, 9b, 10a, 10b, 11a and 11b exhibited higher DPPH scavenging potential (EC50 = 32.7, 53, 36.1, 60, 40.6 and 67 µM, respectively) than ascorbic acid (EC50 = 86.58 µM). While targets 9a, 10a and 11a (RP50 = 52.19, 59.16 and 52.25 µM, respectively) exhibited better reducing power than the ascorbic acid (RP50 = 84.66 µM). Computational analysis had been utilized to prophesy the bioactivity and molecular properties of the target compounds. Conclusion: To predict the binding manner of the novel derivatives as antioxidants, in-silico docking study had been performed to all the newly prepared compounds inside superoxide dismutase (SOD) and catalase (CAT) active site. The most active antioxidant candidate 9a (EC50 = 32.7 µM, RP50 = 52.19 µM) displayed excellent binding with Lys134 amino acid residing at Cu-Zn loop of SOD with binding energy score = -7.54 Kcal/mol thereby increase SOD activity and decrease reactive oxygen species.

Repurposing FDA-approved Drugs Targeting SARS-CoV2 3CLpro: a study by applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking

Background: Since the end of 2019, the etiologic agent SAR-CoV-2 responsible for one of the most significant epidemics in history has caused severe global economic, social, and health damages. The drug repurposing approach and application of Structure-based Drug Discovery (SBDD) using in silico techniques are increasingly frequent, leading to the identification of several molecules that may represent promising potential. Method: In this context, here we use in silico methods of virtual screening (VS), pharmacophore modeling (PM), and fragment-based drug design (FBDD), in addition to molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM -PBSA) calculations, and covalent docking (CD) for the identification of potential treatments against SARS-CoV-2. We initially validated the docking protocol followed by VS in 1,613 FDA-approved drugs obtained from the ZINC database. Thus, we identified 15 top hits, of which three of them were selected for further simulations. In parallel, for the compounds with a fit score value ≤ of 30, we performed the FBDD protocol, where we designed 12 compounds Result: By applying a PM protocol in the ZINC database, we identified three promising drug candidates. Then, the 9 top hits were evaluated in simulations of MD, MM-PBSA, and CD. Subsequently, MD showed that all identified hits showed stability at the active site without significant changes in the protein's structural integrity, as evidenced by the RMSD, RMSF, Rg, SASA graphics. They also showed interactions with the catalytic dyad (His41 and Cys145) and other essential residues for activity (Glu166 and Gln189) and high affinity for MM-PBSA, with possible covalent inhibition mechanism. Conclution: Finally, our protocol helped identify potential compounds wherein ZINC896717 (Zafirlukast), ZINC1546066 (Erlotinib), and ZINC1554274 (Rilpivirine) were more promising and could be explored in vitro, in vivo, and clinical trials to prove their potential as antiviral agents.

Design, Molecular Docking, Synthesis, Characterization and Biological Activities of Novel Thiazole Derivatives

Aim: The study aims to design & synthesize novel thiazole derivatives as potent antitubercular agents with minimal side effects. Background: The emergence and rapid spread of multi-drug resistant infectious microbial flora embracing a variety of bacterial as well as mycobacterium strains are causing a threat to public health worldwide. Objective: Owing to the importance, we designed compounds with thiazole functionality coupled with Schiff base and thiosemicarbazide, predicted the molecular properties and antitubercular potency of designed compounds by the in-silico method, and synthesized fifteen novel thiazole analogs, characterized and tested in vivo antitubercular, antibacterial and antioxidant potencies. Methods: Molinspiration online tool was used to predict the molecular properties and molecular docking was used to predict the antitubercular potency. FT-IR, 1H-NMR, 13C-NMR, Mass spectroscopy and bases of elemental analysis are employed to confirm the structure of compounds. 10-Fold serial dilution method, agar streak dilution test and DPPH radical scavenging methods are used to estimate antitubercular, antibacterial and antioxidant potency of title analogs, respectively. Results: Multi-step synthesis was used to synthesize a variety of novel thiazole derivatives coupled with Schiff base and thiosemicarbazide. Synthesized title compounds displayed a varying degree of antitubercular, antibacterial and antioxidant activities (mild to good). The title compounds possessing deactivating group exhibited superior activities than activating group, while unsubstituted analogs displayed intermediate activities. In addition, para-substituted analogs showed slightly higher activity than the corresponding meta substituted analogs. Conclusion: Among fifteen tested title compounds, the potent compound of this series was found to be 1-(4-nitrobenzylidene)-4-(4-(4-methoxyphenyl)thiazol-2-yl)thiosemicarbazide (BTS14), which might be extended as a novel class of antitubercular and antibacterial agents.

Synthesis of 5(S)-Methyl-L-Proline containing Peptidomimetic Compounds and their In-Vitro Evaluation for Dipeptidyl Peptidase-4 Inhibition

Background: Type 2 diabetes mellitus (T2DM), which is the epidemic of the 21st century, has affected millions of people worldwide. Traditional methods available for the treatment are associated with various side effects. Among the newer therapies, DPP-4 (Dipeptidyl peptidase-4) inhibition has been a promising therapy for the past decade with the scope of further development, especially in peptidomimetics. Objective: 5(S)-methyl-L-proline containing peptidomimetic compounds were designed in the previous work. The designed compounds were synthesized and characterized by spectral methods, such as mass spectrometry, 1H NMR, and 13C NMR (Nuclear magnetic resonance) spectroscopy. The purity of the final compounds was determined by high-performance liquid chromatography (HPLC). The synthesized compounds were in vitro evaluated for their DPP-4 inhibitory activity. Method: Compounds were peptide in nature and were synthesized using the conventional synthesis approach, where peptide synthesis was done using an acid-amine coupling reagent. They were evaluated through fluorimetric enzyme-based assay using a DPP-4 inhibitor screening kit. Moreover, the CLARIOstar microplate reader instrument was used to measure fluorescence. Results: 5(S)-methyl-L-proline containing 13 compounds were synthesized. All of them were characterized for structural integrity using spectral methods. They had HPLC purity of more than 95% and were evaluated for DPP-4 inhibition. Compounds 001, 007, 010, 011, 014, and 017 were found to have good inhibition than others. These compounds were further evaluated at different concentrations to develop a linear correlation coefficient (R2). Conclusion: Six compounds were found to have good DPP-4 inhibition, hence it further opens the possibility of developing DPP-4 inhibitor-containing 5(S)-methyl-L-proline.

Potential Inhibitors Identification of Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Angiotensin-Converting Enzyme 2 and Main Protease from Anatolian Traditional Plants

Background: The 2019 novel coronavirus disease (COVID-19) has caused a global health catastrophe by affecting the whole human population around the globe. Unfortunately, there is no specific medication or treatment for COVID-19 currently available. Objective: It’s extremely necessary to apply effective drug treatment in order to end the pandemic period and return daily life to normal. In terms of the urgency of treatment, rather than focusing on the discovery of novel compounds, it is critical to explore the effects of existing herbal agents with proven antiviral properties on the virus. Method: Molecular docking studies were carried out with three different methods, Glide extra precision (XP) docking, Induced Fit docking (IFD), and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA), to determine the potential effects of 58 phytochemicals in the content of Rosmarinus officinalis, Thymbra spicata, Satureja thymbra, and Stachys lavandulifolia plants -have antiviral and antibacterial effects- against Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) enzymes. Results: 7 compounds stand out among all molecules by showing very high binding affinities. According to our findings, the substances chlorogenic acid, rosmarinic acid, and rosmanol exhibit extremely significant binding affinities for both Mpro and ACE2 enzymes. Furthermore, it was discovered that carnosic acid and alpha-cadinol showed potential anti-Mpro activity, whereas caffeic acid and carvacrol had promising anti-ACE2 activity. Conclusion: Chlorogenic acid, rosmarinic acid, rosmanol, carnosic acid, alpha-cadinol, caffeic acid, and carvacrol compounds have been shown to be powerful anti-SARS-COV-2 agents in docking simulations against Mpro and ACE2 enzymes, as well as ADME investigations.

Antioxidant, antimicrobial, and molecular docking studies of novel chalcones and Schiff bases bearing 1, 4-naphthoquinone moiety

Background: The 1,4-naphthoquinone ring has attracted prominent interest in the field of medicinal chemistry due to its potent pharmacological activity as antioxidant, antibacterial, antifungal, and anticancer. Objective: Herein, a series of new Schiff bases (4-6) and chalcones (8a-c & 9a-d) bearing 1,4-naphthoquinone moiety were synthesized in good yields and were subjected to in-vitro antimicrobial, antioxidant, and molecular docking testing. Methods: A facile protocol has been described in this study for the synthesis of new derivatives (4-7, 8a-c, and 9a-d) bearing 1,4-naphthoquinone moiety. The chemical structures of all the synthesized compounds were identified by 1H-NMR, 13C-NMR, MS, and elemental analyses. Moreover, these derivatives were assessed for their in-vitro antimicrobial activity against gram-positive, gram-negative bacteria, and fungal strains. Further studies were conducted to test their antioxidant activity using DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging assay. Molecular docking studies were realized to identify the most likely interactions of the novel compounds within the protein receptor. Results: The antimicrobial results showed that most of the compounds displayed good efficacy against both bacterial and fungal strains. The antioxidant study revealed that compounds 9d, 9a, 9b, 8c, and 6 exhibited the highest radical scavenging activity. Docking studies of the most active antimicrobial compounds within GLN- 6-P, recorded good scores with several binding interactions with the active sites. Conclusion: Based on the obtained results, it was found that compounds 8b, 9b, and 9c displayed the highest activity against both bacterial and fungal strains. The obtained findings from the DPPH radical scavenging method revealed that compounds 9d and 9a exhibited the strongest scavenging potential. The molecular docking studies proved that the most active antimicrobial compounds 8b, 9b and 9c displayed the highest energy binding scores within the glucosamine-6-phosphate synthase (GlcN-6-P) active site.

Screening of natural compounds against SOD1 as a therapeutic target for Amyotrophic lateral sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is an uncommon and progressive neurological illness that predominantly includes the neurons liable for voluntary muscular activities. Starting from weakness or stiffness in muscles, this gradually exploits the strength and ability to speak, eat, move and even breathe. Its exact mechanism is still not clear, but mutations in the SOD1 gene have been reported to cause ALS, and some studies also found involvement of SOD1 overexpression in the pathogenesis of ALS. As of now, there is no remedy available for its cure. Objective: To identify the potential inhibitors for wild type 1HL5, l113T mutant, and A4V mutant of SOD1 (Superoxide Dismutase 1) protein. Methods: In this study, in silico approaches like virtual screening, molecular docking, pharmacokinetic parameters study, and molecular dynamics simulation were used to identify the best potential inhibitors against wild type and mutant SOD1 protein. Methods: In this study, in silico approaches like virtual screening, molecular docking, pharmacokinetic parameters study, and molecular dynamics simulation were used to identify the best potential inhibitors against wild type and mutant SOD1 protein. Results: On the basis of binding affinity and binding energy, the top three compounds ZINC000095486263, ZINC000095485989, and ZINC000028462577, were observed as the best compounds. In the case of 1HL5, ZINC000095486263 had the highest binding affinity with docking score -10.62 Kcal/mol, 1UXM with ZINC000095485989 had the highest docking score -12.03 Kcal/mol, and 4A7V with ZINC000028462577 was found -11.72 Kcal/mol. Further, Molecular Dynamic simulations (MDS) results showed that the ZINC000095486263, ZINC000095485989, and ZINC000095485956 compounds were formed a stable complex with 1HL5, 1UXM, and 4A7V, respectively Conclusions: : After analyzing the results, we hereby conclude that naturals compounds such as ZINC000095486263, ZINC000095485989, and ZINC000095485956 could be used as a potential inhibitor of 1HL5, 1UXM, and 4A7V, respectively, for ALS treatment and could be used as a drug. Further, In vivo/vitro study of these compounds could be a future direction in the field of drug discovery.

Computational Study Reveals PARP1 and P2Y1 Receptors as Prospective Targets of Withaferin-A for Cardiovascular Diseases

Background: Cardiovascular Diseases (CVDs) remain the leading cause of death worldwide, which urges for effective strategies of prevention and treatment. Withaferin-A (WFA), the key metabolite identified in Withania somnifera, has been known for its cardioprotective properties. Although it has been traditionally employed to treat cardiovascular ailments for several decades, its exact mechanism of action still remains unexplained Objective: The current study modelled and scored the interactions of WFA with nine prospective protein-targets associated with cardiovascular diseases through molecular docking and DSX-scoring. Methods: Molecular docking was carried out using Autodock and DSX-scoring was carried out using DSX standalone software. WFA was observed to favorably interact with six targets before DSX-based rescoring, but only with Poly (ADP-Ribose) Polymerase-1 and P2Y Purinoceptor-1 after DSX-based rescoring. The spatial orientation, physicochemical properties and structural features of Withaferin-A were compared with that of these approved drugs by pharmacophore modeling and hierarchical clustering Results: The results of molecular docking, DSX-based rescoring and complete pharmacophore modeling together revealed that PARP1 and P2Y1 receptor could be prospective targets of WFA for the treatment of CVD. Conclusion: Simulation using GROMACS has revealed that WFA forms a more stable complex with PARP1 and will be useful in developing the broad-spectrum drugs against cardiovascular diseases. Further computational studies through machine learning and network pharmacology methods can be carried out to improve Withaferin-A compound features by incorporating additional functional groups necessary for molecular recognition of the target genes in network responsible for cardiovascular diseases.

Molecular Docking of the Terpenes in Gorgonian Corals to COX-2 and iNOS Enzymes as Anti-Inflammatory

Background: The inflammatory pathway is induced by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) enzymes, so it requires the development of its inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), but they have side effects. Therefore, the discovery and development of natural medicine as a lead compound are needed. The gorgonian corals have been reported to contain cyclic diterpenes with anti-inflammatory activities. The specific anti-inflammatory inhibitor potential has not been reported regarding these secondary metabolites, whether in COX-2 or iNOS. Thus, the in silico method is the right alternative. Objective: This study aimed to determine the potency of fifteen terpenes of the various gorgonian corals to COX-2 and iNOS enzymes as an anti-inflammatory Methods: Molecular docking was performed using ChemDraw Ultra 12.0, Chem3D Pro 12.0, Biovia Discovery Studio 2016 Client®, Autodock Tools 4.2, prediction pharmacokinetics (Pre-ADMET), and oral administration (Lipinski rule of five). Results: Potential terpenes based on ΔG (kcal/mol) and Ki (nM) to COX-2 were gyrosanol B (-10,32; 27,15), gyrosanol A (-10,20; 33,57), echinolabdane A (-9,81; 64,76). Only nine terpenes were specific to COX-2 active sites, while for iNOS were palmonine F (-7.76; 2070), briarenol C (-7.55; 2910), and all test compounds binding to the iNOS active sites. Pre-ADMET prediction obtained that HIA was very excellent (70–100%), Caco-2 had moderate permeability (4–70 nm sec-1), and PPB had strong binding (> 90%). Eight terpenes qualified for the Lipinski rule of five. Conclusion: NOS was a specific target for terpenes based on the free energy of binding (ΔG).