INTERAKSI MOLEKULER INHIBITOR DIPEPTIDYL PEPTIDASE-IV (DPP-IV) DARI PROTEIN SUSU KAMBING SECARA IN SILICO SEBAGAI KANDIDAT ANTIDIABETES

Dipeptidyl peptidase-IV (DPP-IV) merupakan salah satu target dalam pengobatan diabetes tipe-2. Beberapa obat golongan gliptin yang tersedia secara komersial seperti sitagliptin, anagliptin, linagliptin, saxagliptin, dan alogliptin secara khusus digunakan sebagai inhibitor DPP-IV untuk pasien diabetes. Saat ini, penggunaan peptida pada protein susu kambing untuk mengobati diabetes telah dilaporkan dalam berbagai percobaan in vitro. Namun, pemahaman tentang interaksi molekuler penghambatan peptida tersebut terhadap DPP-IV masih kurang. Penelitian ini bertujuan untuk melakukan identifikasi, evaluasi, dan eksplorasi mengenai afinitas beberapa molekul peptida tersebut, yaitu MHQPPQPL, SPTVMFPPQSVL, VMFPPQSVL, INNQFLPYPY, dan AWPQYL terhadap makromolekul DPP-IV dengan menggunakan simulasi penambatan molekuler berbasis protein-peptida. Sekuensing peptida terlebih dahulu dilakukan pemodelan dengan menggunakan server PEP-FOLD. Konformasi terbaik dipilih untuk dilakukan studi interaksi terhadap makromolekul DPP-IV dengan menggunakan software HPEPDock. Identifikasi lebih lanjut dilakukan terhadap interaksi molekuler yang terbentuk dengan menggunakan software BIOVIA Discovery Studio 2020.  Berdasarkan hasil dari penambatan molekuler berbasis protein-peptida diperoleh bahwa molekul peptida INNQFLPYPY memiliki afinitas yang paling baik terhadap makromolekul DPP-IV, yaitu dengan nilai energi bebas ikatan −923,46 kJ/mol. Dengan demikian, peptida tersebut diprediksi dapat digunakan sebagai kandidat inhibitor DPP-IV

In silico Identification of Characteristics Spike Glycoprotein of SARS-CoV-2 in the Development Novel Candidates for COVID-19 Infectious Diseases

Background: The emergence of infectious diseases caused by SARS-CoV-2 has resulted in more than 90,000 infections and 3,000 deaths. The coronavirus spike glycoprotein encourages the entry of SARS-CoV-2 into cells and is the main target of antivirals. SARS-CoV-2 uses ACE2 to enter cells with an affinity similar to SARS-CoV, correlated with the efficient spread of SARS-CoV-2 among humans.Objective: In the research, identification, evaluation, and exploration of the structure of SARS-CoV and SARS-CoV-2 spike glycoprotein macromolecules and their effects on Angiotensin-Converting Enzyme 2 (ACE-2) using in silico studies.Methods: The spike glycoproteins of the two coronaviruses were prepared using the BIOVIA Discovery Studio 2020. Further identification of the three-dimensional structure and sequencing of the macromolecular spike glycoprotein structure using Chimera 1.14 and Notepad++. To ensure the affinity and molecular interactions between the SARS-CoV and SARS-CoV-2 spike glycoproteins against ACE-2 protein-protein docking simulations using PatchDock was accomplished. The results of the simulations were verified using the BIOVIA Discovery Studio 2020.Results: Based on the results of the identification of the macromolecular structure of the spike glycoprotein, it was found that there are some similarities in characteristics between SARS-CoV and SARS-CoV-2. Protein-protein docking simulations resulted that SARS-COV-2 spike glycoprotein has the strongest bond with ACE-2, with an ACE score of −1509.13 kJ/mol.Conclusion: Therefore, some information obtained from the results of this research can be used as a reference in the development of SARS-CoV-2 spike glycoprotein inhibitor candidates for the treatment of infectious diseases of COVID-19

Analysis of SARS-CoV-2 Spike Protein as The Key Target in the Development of Antiviral Candidates for COVID-19 through Computational Study

The recent public health crisis is threatening the world with the emergence of the spread of the new coronavirus 2019 (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus originates from bats and is transmitted to humans through unknown intermediate animals in Wuhan, China in December 2019. Advances in technology have opened opportunities to find candidates for natural compounds capable of preventing and controlling COVID-19 infection through inhibition of spike proteins of SARS-CoV-2. This research aims to identify, evaluate, and explore the structure of spike protein macromolecules from three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) and their effects on Angiotensin-Converting Enzyme 2 (ACE-2) using computational studies. Based on the identification of the three spike protein macromolecules, it was found that there was a similarity between the active binding sites of ACE-2. These observations were then confirmed using a protein-docking simulation to observe the interaction of the protein spike to the active site of ACE-2. SARS-COV-2 spike protein has the strongest bond to ACE-2, with an ACE score of ?1341.85 kJ/mol. Therefore, some of this information from the results of this research can be used as a reference in the development of competitive inhibitor candidates for SARS-CoV-2 spike proteins for the treatment of COVID-19 infectious diseases

MOLECULAR DOCKING, MOLECULAR DYNAMICS, AND IN SILICO TOXICITY PREDICTION STUDIES OF COUMARIN, N-OXALYLGLYCINE, ORGANOSELENIUM, ORGANOSULFUR, AND PYRIDINE DERIVATIVES AS HISTONE LYSINE DEMETHYLASE INHIBITORS

Objective: Prostate cancer is the second most common cancer in men. One of the efforts in the treatment of prostate cancer is by inhibiting histone lysine demethylase. Derivative compounds of coumarine, N-oxalylglycine, organoselenium, organosulfur, and pyridine have been reported to be active against two types of histone lysine demethylase (KDM) enzymes, KDM4E and KDM5B. This study aims to study the interactions of these derivatives with KDM.Methods: In this study, we performed computational studies, including molecular docking and molecular dynamics (MDs) simulations, and toxicity prediction, to assess the compounds' activities toward three other KDM enzymes, KDM1A, KDM4A, and KDM4C.Results: Molecular docking simulations showed that a derivative compound of N-oxalylglycine, (R)-3-(4-[benzyloxy]phenyl)-2-(carboxyformamido) propanoic acid, and a derivative compound of pyridine, 3-(4-methoxybenzylamino)pyridine-2,4-dicarboxylic acid, has the highest affinity toward KDM. These results were confirmed in MDs studies which showed strong interactions at the active site of the five receptors. Toxicity prediction results show that the derivative compounds of coumarine, N-oxalylglycine, organoselenium, organosulfur, and pyridine are classified in category (high class), which suggests that the safety is not guaranteed, but is likely, not carcinogenic and nongenotoxic.Conclusion: Several coumarin, N-oxalylglycine, organoselenium, organosulfur, and pyridine derivative compounds are predicted to be able to interact strongly with KDM. The results in this study are useful for further studies in the development of novel anticancer drugs that target KDM

Magainin as an Antiviral Peptide of SARS-CoV-2 Main Protease for Potential Inhibitor: An In Silico Approach

The new coronavirus (SARS-CoV-2), which caused the global pandemic Coronavirus Disease-2019 (COVID-2019), has infected nearly 206 countries. There is still little information about molecular compounds that can inhibit the development of infections caused by this disease. It is crucial to discover competent natural inhibitor candidates, such as antiviral peptides, because they have a variety of biological activities and have evolved to target biochemical machinery from different pathogens or host cell structures. In silico studies will be carried out, including protein-peptide docking and protein-protein docking, to identify, evaluate, and explore the affinity and molecular interactions of the Magainin-1 and Magainin-2 peptide molecules derived from frog skin (Xenopus laevis) to the main protease macromolecule (Mpro) SARS-CoV-2, and its effect on the ACE-2 receptor (Angiotensin Converting Enzyme-2 Receptor). Protein-peptide docking simulations show that both peptide molecules have a good affinity for the active site area of the SARS-CoV-2 Mpro macromolecule. These results were then confirmed using protein-protein docking simulations to observe the ability of the peptide molecule in preventing attachment to the ACE-2 receptor surface area. In silico studies show that Magainin-2 has the best affinity, with a bond free energy value of −3054.53 kJ/mol. Then the protein-protein docking simulation provided by Magainin-2 prevented the attachment of ACE-2 receptors, with an ACE score of 1697.99 kJ/mol. Thus, through in silico research, the Magainin peptide molecule can be further investigated in the development of new antiviral peptides for the treatment of infectious diseases of COVID-19

Identification of the Glimepiride and Metformin Hydrochloride Physical Interaction in Binary Systems

Glimepiride is often combined with metformin HCl as an oral antidiabetic in type II diabetes mellitus, which provides a complementary and synergistic effect with multiple targets for insulin secretion. Glimepiride includes class II of BCS, which solubility practically insoluble in water but high permeability, which will impact the drug's small bioavailability. In contrast, metformin HCl includes class III of BCS, which has a high solubility in water, but low permeability is absorbed approximately 50-60% in the digestive tract given orally. The co-crystallization method can be used to improve the glimepiride solubility properties and the permeability properties of metformin HCl by interrupting glimepiride with metformin HCl physically. This study aims to identify the physical interactions between glimepiride and metformin HCL using a thermal analysis of Differential Scanning Calorimetry (DSC) and then confirmed by a computational approach. Identifying the physical interactions between glimepiride and metformin HCL was carried out by plotting the melting points generated from the endothermic peaks of the DSC thermogram at various compositions versus the mole ratios of the two were further confirmed by the computational approach using PatchDock. The results of the phase diagram analysis of the binary system between glimepiride and metformin HCl show a congruent pattern, which indicates the formation of co-crystal or molecular compounds at a 1 : 1 mole ratio at 228°C. Computational approach results showed that the interaction between glimepiride and metformin HCl did not form new compounds but heterosinton formation that was stable in molecular dynamics simulations

The Inhibition of Angiotensin-Converting Enzyme 2 Receptors of SARS-CoV-2 Through Mucroporin Derived from Scorpion Venom

The SARS-CoV-2 virus that causes COVID-19 has a spike glycoprotein that can bind to a host cell receptor, angiotensin-converting enzyme 2 (ACE-2). This plays an important role in the entry of viral cells. Therefore, targeting of the ACE- 2 receptor holds promise as a potential target for anti-viral interventions to prevent and inhibit COVID-19. This study aims to focus on in silico studies to screen alternative drugs that can block ACE-2 receptor properties as a receptor for SARS- CoV-2. It is a potential therapeutic target for COVID-19 using the bioactive peptide Mucroporin which is derived from scorpion venom. There were four sequences of Mucroporin peptides modeled using the PEP-FOLD 3.5 server. The protein- peptide-based molecular docking simulations were used to identify and evaluate the actions of Mucroporin against ACE-2 receptors using PatchDock. The best response is then further observed using BIOVIA Discovery Studio 2020. This study revealed that Mucroporin and Mucroporin-S1 gave the best docking scores compared to Mucroporin-M1 and Mucroporin-S2, with the binding free energy values of −943.53 kJ/mol, −162.42 kJ/mol, 867.80 kJ/mol and 43.14 kJ/mol respectively. This study reveals for the first time that Mucroporin and Mucroporin-S1 are functional inhibitors of ACE-2 and as such, that components of scorpion venom can be used as potential inhibitors to the ACE-2 receptor of SARS-CoV-2. Keywords: SARS-CoV-2; COVID-19; Angiotensin-Converting Enzyme 2 (ACE-2); Mucroporin; In Silico Stud

Studi Interaksi Senyawa Turunan Saponin dari Daun Bidara Arab (Ziziphus spina-christi L.) sebagai Antiseptik Alami secara In Silico

Christinin merupakan senyawa turunan glikosida saponin yang paling banyak terdapat dalam daun bidara arab (Ziziphus spina-christi L.). Terdapat empat tipe christinin yaitu christinin-A, B, C, dan D yang diduga memiliki aktivitas sebagai antimikroba yang efektif terhadap bakteri dan jamur, seperti Staphylococcus epidermidis, Echerichia coli, dan Candida albicans yang sering menyebabkan infeksi pada permukaan kulit yang biasanya dapat diatasi dengan penggunaan cairan antiseptik. Penelitian ini bertujuan untuk mengidentifikasi, mengevaluasi serta mengeksplorasi afinitas dan interaksi molekular antara senyawa christinin-A, B, C, dan D terhadap makromolekul target pada Staphylococcus epidermidis, Echerichia coli dan Candida albicans dengan menggunakan simulasi penambatan molekular secara in silico. Molekul senyawa uji terlebih dahulu dioptimasi geometri dengan menggunakan perangkat lunak GaussView 5.0.8 dan Gaussian09. Konformasi terbaik dipilih untuk dilakukan studi interaksi terhadap makromolekul target dengan menggunakan perangkat lunak MGLTools 1.5.6 yang dilengkapi dengan AutoDock 4.2. Interaksi yang terbentuk selanjutnya diamati dengan menggunakan perangkat lunak BIOVIA Discovery Studio 2020.  Berdasarkan hasil dari simulasi penambatan molekular, senyawa christinin memiliki afinitas yang baik terhadap makromolekul target pada Staphylococcus epidermidis, Echerichia coli dan Candida albicans. Dengan demikian, senyawa tersebut diprediksi dapat digunakan sebagai kandidat komponen utama dari antiseptik alami

Biological activity, molecular docking, and ADME predictions of amphibine analogues of Ziziphus spina-christi towards SARS-CoV-2 Mpro

The main protease of the SARS-CoV-2 virus, SARS-CoV-2 Mpro, can be discovered as a promising target to treat the COVID-19 pandemic. The peptide-based inhibitors may present better options than small molecules to inhibit SARS-CoV-2 Mpro. Ziziphus spina-christi species reported have a peptide-based of alkaloids group, i.e., amphibine whose analogues can be identified the potential as an inhibitor of SARS-CoV-2 Mpro. The compound structure was drawn and optimized using semi-empirical AM-1 method using Quantum ESPRESSO v.6.6, while the biological activity using PASS. Prediction server and molecular docking simulation using MGLTools 1.5.6 with AutoDock 4.2 were performed. Afterward, the ADME profiles were predicted using the SWISS-ADME server. PASS server was predicting amphibine B-F and H showed potency both as antiviral and as a protease inhibitor. The molecular docking simulation of amphibine analogues showed lower binding energy than the native ligand. The binding energy of the native ligand was −7.69 Kcal/mol compared to the lowest binding energy of amphibine analogues was −10.10 Kcal/mol (amphibine-F). The ADME prediction showed that amphibine-F has the best bioavailability as an oral drug, amphibine-B, C, and D have good bioavailability, and amphibian-E and H have poor bioavailability. Concluded, amphibine B-F and H of amphibine analogues showed potency as COVID-19 treatment targeting SARS-CoV-2 Mpro

In Silico Activity Identification of Cyclo Peptide Alkaloids from Zizyphus Spina-Christi Species Against Sars-Cov-2 Main Protease

The COVID-19 has spread worldwide and become an international pandemic. The promising target for drug discovery of COVID-19 was SARS-CoV-2 Main Protease (Mpro), that has been successfully crystallized along with its inhibitor. The discovery of peptide-based inhibitors may present better options than small molecules for inhibitor SARS-CoV-2 Mpro. Natural compounds have such a wide potential and still few explored, Zizyphus spina-christi is one of the medicinal plants that have many pharmacological activities and contains a peptide compound from alkaloids class, i.e. cyclopeptide alkaloids, that is interesting to explore as SARS-CoV-2 Mpro inhibitor. The compound structure was drawn and optimized using density functional theory 3-21G method. The protein chosen was the high resolution of SARS-CoV-2 MPro receptor (1.45 Å) with PDB ID: 6WNP, in complex with boceprevir. Molecular docking simulation was performed using Autodock4 with 100 numbers of GA run, the validation methods assessed by RMSD calculation. Furthermore, the prediction of pharmacological activity spectra was carried out using the PASS Prediction server. The results showed RMSD value was 1.98 Å, this docking method was valid. The binding energy of all compounds showed better results than the native ligand (Boceprevir). The in silico PASS prediction results indicated that all compounds showed antiviral activity. Some compounds showed protease inhibitory activity, i.e Ambiphibine-H, Franganine, and Mauritine-A, and the highest Pa (Predicted activity) value showed by Mauritine-A compounds. It can be concluded that the cyclopeptide compounds of Zizyphus spina-christi were indicated to have a potential as COVID-19 therapy targeting SARS-CoV-2 Mpro