Molecular Docking Studies of Dihydropyridazin-3(2H)-one Derivatives as Anticonvulsant Agents

Molecular docking is the identification of ligand’s correct binding geometry i.e. pose in the binding site and estimation of its binding affinity for rational design of drug molecule. The current study endeavored the high throughput in silico screening of 56 derivatives of dihydropyridazin-3(2H)-one docked with human cytosolic branched chain amino transferase using PyRx-virtual screening tool. Out of 56 compounds, almost all the test compounds showed very good binding affinity score. Gabapentin was used as standard drug which shows binding affinity of -6.2. On the basis of H-bond interactions, compounds 3, 9, 11, 25, 26, 31, 34, 39, 47, 48, 51, 54, 56 were found to be potent outcome for anticonvulsant activity. Compounds 11, 25, 39, 56 showed excellent H-bond interactions with protein active site, Among which compound 11 showed the outstanding interactions with acceptable bond length 2.34, 2.57, 2.62, 3.03 Å.

Affinity Scores: An Individual-centric Fingerprinting Framework for Neuropsychiatric Disorders

Background: Population-centric frameworks of biomarker identification for psychiatric disorders focus primarily on comparing averages between groups and assume that diagnostic groups are (1) mutually-exclusive, and (2) homogeneous. There is a paucity of individual-centric approaches capable of identifying individual-specific fingerprints across multiple domains. To address this, we propose a novel framework, combining a range of biopsychosocial markers, including brain structure, cognition, and clinical markers, into higher-level fingerprints, capable of capturing intra-illness heterogeneity and inter-illness overlap. Methods: A multivariate framework was implemented to identify individualised patterns of brain structure, cognition and clinical markers based on affinity to other participants in the database. First, individual-level affinity scores defined a neighbourhood for each participant across each measure based on variable-specific hop sizes. Next, diagnostic verification and classification algorithms were implemented based on multivariate affinity score profiles. To perform affinity-based classification, data were divided into training and test samples, and 5-fold nested cross-validation was performed on the training data. Affinity-based classification was compared to weighted K-nearest neighbours (KNN) classification. K-means clustering was used to create clusters based on multivariate affinity score profiles. The framework was applied to the Australian Schizophrenia Research Bank (ASRB) dataset. Results: Individualised affinity scores provided a fingerprint of brain structure, cognition, and clinical markers, which described the affinity of an individual to the representative groups in the dataset Diagnostic verification capability was moderate to high depending on the choice of multivariate affinity metric. Affinity score-based classification achieved a high degree of accuracy in the training, nested cross-validation and prediction steps, and outperformed KNN classification in the training and test datasets. Conclusion: Affinity scores demonstrate utility in two keys ways: (1) Early and accurate diagnosis of neuropsychiatric disorders, whereby an individual can be grouped within a diagnostic category/ies that best matches their fingerprint, and (2) identification of biopsychosocial factors that most strongly characterise individuals/disorders, and which may be most amenable to intervention.

Molecular docking studies of dihydropyridazin-3(2H)-one derivatives as Antifungal, antibacterial and anti-helmintic agents

Molecular docking is the identification of ligand’s correct binding geometry i.e pose in the binding site and estimation of its binding affinity for the rational design of drug molecule. The current study endeavored the high throughput insilico screening of 24 compounds docked with their respective protein using PyRx-Virtual Screening Tool software. Out of 24 compounds, almost all test compounds showed a very good binding affinity score. Fluconazole was used as a standard drug in case of Antifungal, Ciprofloxacin in case of Antibacterial, and Albendazole in case of Antihelmintics. More negative is the binding free energy score, more favorable is the pose for binding to protein active site. Based on H-bond interactions of these 24 compounds, Compounds 3a5, 3c3, 3d5, 3d6 were found to be the similar outcome for antifungal activity as fluconazole, Compound3a1 for antibacterial, and Compounds 3b5, 3d6 for the antihelmintic agent. Furthermore, the affinity of any small ligand molecules can be considered as an extraordinary tool in the field of drug design and offer imminent in future examination to build up potent antimicrobial agents.

Pharmacophore Based Design Of Probable Fgfr-1 Inhibitors From The 3d Crystal Structure Of Infigratinib - A Drug Used In The Treatment Of Cholangiocarcinomas

Background: Pemigatinib (INCB054828) and Infigratinib (BGJ398) are the few selective drugs that are approved by the FDA to treat cholangiocarcinoma, a rare form of bile duct cancer. Infigratinib is a pan FGFR inhibitor and has been found promising in Phase-3, first-line PROOF clinical trial. So, screening drug-like compounds having similar pharmacophoric features like infigratinib is the inspiration of the present work. Objective: The objective was to identify drug-like compounds with similar pharmacophoric features as in infigratinib. The compounds screened through the 3D query pharmacophore of infigratinib were also predicted for ADMET properties so that the compounds may have good bioavailability. Method: A pharmacophore was generated from the crystal structure of infigratinib with several pharmacophoric features such as hydrogen bond donor, hydrophobic, positive ionizable, and ring aromatic. MayBridge database containing 65,263 compounds was used for virtual screening (VS) using LibDock. The initial Hit compounds were subjected to ADMET predictions. Finally, two Hit compounds were selected and docked with the FGFR-1 receptor to predict the interaction of the ligand atoms with the amino acid residues of the receptor's active site. Result: The fit score for infigratinib, N-(4-fluorophenyl)-2-(5-((2-(4-methoxy-2,5-dimethylphenyl)-2-oxoethyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)acetamide (Hit-1) and 4-(4-((2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)pyridin-2-yl)-1-methylpiperazin-1-ium (Hit-4) is 4.58901, 4.36649, and 3.71732, respectively. The LibDock score of infigratinib, Hit-1, and Hit-4 is 122.474, 123.289, and 123.353, respectively. The binding affinity score (-PLP1) of infigratinib, Hit-1, and Hit-4 is -143.19, -102.72, and -91.71. Conclusion: The present study concluded that the two compounds designated as Hit-1 and Hit-4 have been identified as binders of FGFR-1, and Hit-4 occupies the whole pharmacophoric space of infigratinib, and both the compounds LibDock scores are better than the infigratinib. Other: The two compounds Hit-1 and Hit-4 may be synthesized and studied for their enzyme inhibition assay on FGFR-1 and biologically evaluated on different cell lines for Cholangiocarcinoma.

AtomNet PoseRanker: Enriching Ligand Pose Quality for Dynamic Proteins in Virtual High Throughput Screens

Structure-based, virtual High Throughput Screening (vHTS) methods for predicting ligand activity in drug discovery are important when there are no or relatively few known compounds that interact with a therapeutic target of interest. State-of-the-art computational vHTS necessarily relies on effective methods for pose sampling and docking to generate an accurate affinity score from the docked poses. However, proteins are dynamic; in vivo, ligands bind to a conformational ensemble. In silico docking to the single conformation represented by a crystal structure can adversely affect the pose quality. Here we introduce AtomNet PoseRanker, a graph convolutional network trained to identify, and re-rank crystal-like ligand poses from a sampled ensemble of protein conformations and ligand poses. In contrast to conventional vHTS methods that incorporate receptor flexibility, a deep learning approach can internalize valid cognate and non-cognate binding modes corresponding to distinct receptor conformations. AtomNet PoseRanker significantly enriched pose quality in docking to cognate and non-cognate receptors of the PDBbind v2019 dataset. Improved pose rankings that better represent experimentally observed ligand binding modes improve hit rates in vHTS campaigns, and thereby advance computational drug discovery, especially for novel therapeutic targets or novel binding sites.

Molecular Docking Senyawa Vitexin, Ursolic Acid dan Flavonol dalam Tumbuhan Binahong (Andredera Cordifolia (Ten.) Steenis) yang Berpotensi sebagai Penghambat Pertumbuhan COVID-19

Currently, there is no specific treatment for all the COVID-19 patients the procedures that can be done are just a symptomatic and oxygen therapy, Therefore all the people around the world have try to avoid this infection by consuming the potensial plants that can boost our body immunity like Binahong. This study was an in silico experimental. The finale result is the binding affinity score from each compound, for vitexin’s binding affinity score is – 8.0 kcal/mol, ursolic acid – 7.6 kcal/mol and flavonol – 7.8 kcal/mol. The finale result of this procedure also obtained all the amino acid residues that works on the active site of receptor 6LU7 as a main protase of COVID-19, namely THR24, LEU27, HIS41, THR45, SER46, MET49, PHE140, LEU141, ASN142, GLY143, SER144, CYS145, HIS163, MET165, GLU166 and HIS172. In conclusion, the binding affinity of vitexin, ursolic acid and flavonol are higher than remdesivir. Vitexin, ursolic acid and flavonol have a several similar bonds, particularly the van der waals bond and hydrogen bond.Keywords: Molecular docking, COVID-19, binahong, flavonoid Abstrak: Saat ini belum tersedia rekomendasi tatalaksana khusus bagi pasien COVID-19, termasuk antivirus atau vaksin dan tata laksana yang dapat dilakukan adalah terapi simtomatik dan karena itulah, masyarakat dunia mencoba banyak cara agar menghindari infeksi virus ini dengan mengolah dan mengonsumsi tumbuhan yang dinilai berpotensi dalam meningkatkan imunitas tubuh seperti tumbuhan Binahong. Penelitian ini menggunakan metode penelitian in silico. Pada hasil akhir penelitian diperoleh nilai binding affinity dari ketiga senyawa yaitu senyawa vitexin - 8.0 kcal/mol, Ursolic Acid -7.6 kcal/mol dan Flavonol -7.8 kcal/mol. Diperoleh data mengenai residu asam amino yang bekerja pada sisi aktif reseptor 6LU7 sebagai main protase COVID-19 yaitu THR24, LEU27, HIS41, THR45, SER46, MET49, PHE140, LEU141, ASN142, GLY143, SER144, CYS145, HIS163, MET165, GLU166, dan HIS172. Sebagai simpulan, binding affinity dari senyawa vitexin, ursolic acid dari flavonol lebih tinggi dari nilai binding affinity remdesivir. Senyawa vitexin, ursolic acid dan flavonol memiliki beberapa jenis ikatan yang sama termasuk ikatan van der Waals dan ikatan hydrogen.Kata Kunci: Molecular docking, COVID-19, binahong, flavonoid

The Role of Justicia Adhatoda as prophylaxis for COVID-19 – Analysis based on docking study

: Coronavirus cause severe harm to the health of both humans as well as animals, creating a major global health problem affecting millions of populations. Considering situational emergency of identifying novel targeted therapy, we have chosen herbal compound Adathoda justice/ vasica which is high potent olden vital compound having key role in various respiratory conditions with multiple beneficial uses. Adathoda is promoted and supported by the Ministry of AYUSH for symptomatic management of respiratory ailments in case of COVID 19. In this study, we focused Adathoda primary active alkaloid vasicine efficacy against coronavirus infectious symptoms, evaluated by in Silico screening studies on virus proteins ACE 2 Receptor, 3CL protease and Spike protein SARS HR1 motif using PyRx tool and AutoDoc 1.5.6. Based on PyRx results, Vasicine with ACE 2 Receptor shown higher docking affinity score -7.1 K/cal respectively when compared to other virus proteins. AutoDoc 1.5.6 screening study report showed that vasicine promotes good inhibitory constant 486.54 mM on 3CL protease more than others. Results reveal that the vasicine could be a potential target for the treatment of COVID 19. This study adds strong evidence to the claim by the advisory released by AYUSH. Based on the results with available literature Adathoda could be a drug helpful in relieving symptoms in non COVID cases those who were quarantined or in lockdown pace thereby reducing pandemic panic and in confirmed asymptomatic or mild cases. For usage in moderate to severe cases this could be an add on therapy with existing modern medical therapy.

Structure-based virtual screening of bioherbicide candidates for weeds in sugarcane plantation using in silico approaches

Weeds in sugarcane have negatively affected the sugar yield rate. Several approaches have been carried out to overcome the weeds, including the usage of diuron as synthetic herbicide. However, the long-term usage of diuron is known to have a negative effect leads to the production of 3,4- Dichloroaniline responsible for soil leach and bioaccumulation. Therefore, this study aimed to find a potential natural herbicide. By mimicking the diuron's mode of action which inhibits the process of photosynthesis through blocking the Photosystem II protein D1 (psbA) of the weeds, fourteen compounds as potential candidate bioherbicides were virtually docked by PyRx v0.9.5 software to the specific site. Three important species of the weeds were chosen including Eleusine indica, Praxelis clematidea, and Momordica charantia. The binding affinity score was further calculated and ranked to screen the top six compounds as bioherbicide candidates. Interaction of each complex and the biological activity prediction were then performed by Discovery Studio software and PASS server, respectively. Aurachin P, Aurachin A, and Cyanobacterin were placed in the top ranked compounds with high binding affinity score around -6 to -9 kcal mol-1 toward the psbA. The amino acid interaction involved in the complex shows 50-90% similar to the control, psbA and diuron complex. Besides, the biological activity prediction of Aurachin P, Aurachin A, and Cyanobacterin exhibits the terms related to the inhibition of photosynthesis process via enzymatic pathway. Thus, the active compounds might have inhibition action in the photosynthesis process and control the weeds in sugarcane.

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole–piperidine (3a)- and azaindole–piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.