IN SILICO DESIGN OF QUINOXALINE BEARING THIAZOLIDINONE DERIVATIVES AS PPARγ AGONIST IN DIABETES MELLITUS

Objective: Diabetes mellitus is a set of metabolic disease in which there is increased blood sugar level over a long period. The objective of the study is in silico design of quinoxaline bearing thiazolidinone derivatives as peroxisome proliferator-activated receptor gamma (PPARγagonist in diabetes mellitus. Methods: In silico design of proposed derivatives was conducted by ACD Lab ChemSketch 12.0 and derivatives obeying Lipinski’s rule of five were selected for docking studies. Docking was carried out using AutoDock Vina software. Results: Molinspiration results revealed that the designed derivatives had physical and chemical properties meant for an orally available drug. Based on the docking results derivatives, QNT1 and QNT2 exhibited high docking score which indicates that these derivatives possess high-affinity and high polar interaction toward protein 1PRG (ligand-binding domain of human peroxisome proliferator-activated receptor gamma). Conclusion: The designed quinoxaline bearing thiazolidinone derivatives were found to possess good binding affinity and good interaction in the binding pocket of target 1PRG, so these derivatives are expected to exhibit good antidiabetic property with minimal side effects

IN SILICO DESIGN OF BENOXAZOLE BEARING AZETIDINONE DERIVATIVES AS VEGFR-2 AGONIST IN CANCER

Objective: Cancer is a group of disease characterized by uncontrolled growth of cells. The objective of the study includes the in silico designing of benzoxazole bearing azetidinone derivatives as Vascular Endothelial Growth Factor 2 in cancer. Methods: In silico design of proposed derivatives was conducted using tools such as AutoDock Vina, ACD Lab ChemSketch ver. 12.0, Prediction of Activity Spectra for Substances online, molinspiration, and Swiss ADME. The derivatives obeying Lipinski’s Rule of Five in accordance with molinspiration were selected for docking studies. Results: The data obtained from molinspiration revealed that the designed derivatives have physical and chemical properties meant for an orally bioavailable drug. From the docking studies derivatives BT1 and BT5 showed high docking score which indicate that these derivatives possess high affinity and high polar interaction towards protein 4DBN. Conclusion: The designed benzoxazole bearing azetidinone derivatives were found to possess good binding affinity and good interaction in the binding pocket of the target 4DBN. Therefore, these derivatives are expected to exhibit good anticancer property with minimal side effects

POTENTIAL DRUG TARGETS FOR ALOIN AND MICRODONTIN: AN IN-SILICO ANALYSIS

ABSTRACTObjective: The aim of this study was to study the interactions of Aloin and microdontin with antimalarial drug targets.Methods: The ADMET properties of Aloin and microdontin were analyzed using LigandScout and Osiris Molecular Property Predictor tools. Theprotein-ligand docking was performed in AutoDock software. AutoDock result was analyzed using PyMol and LigPlot+ software.Results: ADMET analysis suggests no major side effects for both Aloin and microdontin. Docking results show that Aloin had the highest significancewith Plasmodium falciparum calcium-dependent protein kinase (PfCDPK2) with a free binding energy of –8.01 Kcal/Mol, Ki value of 1.35 µM and6 hydrogen bonds. Microdontin had the highest significance toward Glutaredoxin-1 with –8.04 Kcal/Mol, Ki value of 1.28 µM and 3 hydrogen bonds.Conclusion: Based on the observed results for the studied drug targets, the proposed mechanism of action of Aloin is suggestively concluded asPfCDPK2 and for microdontin as glutaredoxin-1.Keywords: Anti-malaria, Aloin, Microdontin, Autodock, Ligandscout

Molecular Docking Analysis of 6-paradol, Zingerone and Zerumbone Against Human Estrogen Receptor Alpha (ERÉ‘)

Molecular docking was done to assess the binding affinity of 6-paradol (6PRD), Zingerone (ZGR) and Zerumbone (ZRB) ligand-ERα complex in comparison to Hydroxytamoxifen (HTMX). Docking results showed that Glu353 and Arg394 active residues forms hydrogen bonding with 6PRD and ZGR. Glu353, Leu387 and Arg394 were the three identical residues found to formed hydrophobic interaction in HTMX-ERα, 6PRD-ERα and ZGR-ERα. HTMX showed lowest binding energy (-10.71 ± 0.43 kcal/mol) followed by ZRB (-8.66 ± 0.04 kcal/mol), 6PRD (-6.92 ± 0.14 kcal/mol) and ZGR (-5.93 ± 0.31 kcal/mol). Inhibition constant (Ki) range of 6PRD-ERα was found to be drastically lower than HTMX-ERα, ZGR-ERα and ZRB-ERα. Based on the docking analysis, the three bioactive compounds were showed to poses low potential as substitute towards tamoxifen. Future study is recommended for analysing 6PRD potential in substituting estradiol as Hormone Replacement Therapy (HRT) for breast cancer

Small Molecule Inhibitor Design for Anaplastic Lymphoma Kinase Inhibition

The Anaplastic Lymphoma Kinase (ALK) gene has been linked to tumorigenesis in a number of human cancers, including anaplastic large cell lymphoma (ALCL) and neuroblastoma. While ALK mutations in ALCL and many other cancers occur as a result of gene fusions with wild type kinase domains, those in neuroblastoma stem from single nucleotide polymorphisms (SNPs) in the kinase domain. These lead to autophosphorylation and constitutive signaling by ALK for cell growth and division, ultimately causing cancer. Crizotinib, an ATP-competitive ALK inhibitor, has proven to be an effective inhibitor of both ALKWT and ALKMutant kinase domains, and is in the middle of clinical trials for neuroblastoma treatment. This review used the PyMOL and AutoDock Vina computational biology programs to predict the binding affinities of Crizotinib, Ceritinib (LDK378), and PF-922 to three different ALK kinase mutations in order to determine the most effective inhibitor. The EGFR inhibitors gefitinib and erlotinib were also analyzed in complex with ALK as negative controls to verify the specificity of the ALK inhibitors. The crystalline complexes were then qualitatively analyzed to uncover the mechanics behind the docking results. Based on the results generated by Vina, PF-922, representative of the second generation of ALK inhibitors, is predicted to be the most effective out of the tested compounds. These results may be used to predict the inhibitor that will require the lowest dosage to achieve the greatest inhibitory effect, hopefully leading to fewer side effects from treatment

POTENSI SENYAWA BULLATALISIN SEBAGAI INHIBITOR PROTEIN LEUKOTRIEN A4 HIDROLASE PADA KANKER KOLON SECARA IN SILICO

ABSTRAK               Kanker kolon merupakan jenis kanker yang dapat menyebabkan kematian. Salah satu penyebabnya adalah pertumbuhan Leukotrien A4 hidrolase yang tidak terkontrol. Leukotrien A4 hidrolase dapat dijadikan target terapi dalam menekan pertumbuhan sel kanker. Bullatalisin merupakan senyawa turunan asetogenin yang memiliki potensi inhibitor terhadap Leukotrien A4 hidrolase. Penelitian ini bertujuan menentukan potensi Bullatalisin sebagai inhibitor secara in silico berdasarkan energi bebas Gibbs (?G), tetapan inhibisi, interaksi ikatan hidrogen serta Root Mean Deviation Square (RMSD). Penelitian dilakukan secara komputasi menggunakan metode molecular docking.Berdasarkan pada hasil analisis visualisasi interaksi docking, menunjukkan adanyainteraksi ikatan antara Bullatalisin dan residu asam amino dari kantung aktif Leukotrien A4 hidrolase. Selain itu nilai energi bebas Gibbs, tetapan inhibisi dan RMSD dari Bullatalisin tidak berbeda secara signifikan dibandingkan dengan ligan standar. Oleh karena itu, Bullatalisin diprediksi berpotensi sebagai inhibitor Leukotrien A4 hidrolase. Kata kunci: bullatalisin, docking, in silico, kanker kolon, leukotrien A4 hidrolas

In silico study of RxLR effectors of Phytophthora infestans HP-10-31, A2 mating type potato late blight pathogen

Phytophthora infestans is one of the most compelling plant pathogen among the scientific community throughout the world. It is the causative agent of potato late blight and responsible for tremendous economic loss worldwide. Pathogenic effector proteins are instrumental in modulating host immunity and disease resistance has been a major concern. In P. infestans, a class of cytoplasmic effectors recognized as RxLR is characterized by highly conserved region and abet in parasitic colonization by modifying the host defense system. We have sequenced an Indian strain of P. infestans HP-10-31 genome and identified several RxLR motif-containing genes.In this study we selected two RxLR effector genes named contig15921_2 and contig06738_6 from this A2 mating type strain. We used I-TASSER server to generate three-dimensional structure and observe the Nicotinamide adenine dinucleotide and S-adenosyl-Lhomocysteine conserve domains. Our in silico study reveals the binding properties of these proteins are favorable with corresponding ligands. This study gives insight into the interaction between putative RxLR effector proteins with its ligand that further aid our understanding of host-pathogen interaction and help in designing new agents to combat the agro pathogenicity

Identification of Benzoxazolinone Derivatives Based Inhibitors for Depression and Pain Related Disorders Using Human Serotonin and Norepinephrine Transporter as Dual Therapeutic Target: A Computational Approach

Pain is commonly associated with depression. Both pain and depression share common biological pathways and neurotransmitters, which has implications for the treatment of both disorders. A drug that could ameliorate both pain and depression could be beneficial in the development of new therapeutics in the management of disorders associated with pain/depression dyad. Alterations in the neurotransmitters namely, serotonin and norepinephrine in the central nervous system (CNS) have been implicated in the pathophysiology of pain and depression. Serotonin and norepinephrine reuptake inhibitors (SNRIs) have been implicated as a novel therapeutic target for a wide range of biological functions, including pain, anxiety and depression. 2-benzoxazolinone (2-BOA) from the mangrove Acanthus ilicifolius and its derivatives have been reported for its analgesic and antidepressant activities. In the present work, docking studies were done on the crystal structure of human transporters of serotonin (hSERT) and on homology modeled human transporters of norepinephrine (hNET) as therapeutic targets of depression and pain related disorders using 2-BOA and its derivatives as potential candidates. A homology model for hNET was constructed using MODELLER and validated. Further docking studies were done on hSERT and hNET using 2-BOA and its structural analogs. The result of the study proposes the possible potential candidate among 2-BOA derivatives that may be further developed as a therapeutic lead compound for use in disorders associated with depression and pain