Docking studies to explore novel inhibitors against human beta-site APP cleaving enzyme (BACE-1) involved in Alzheimer’s disease

Alzheimer’s disease (AD) is one of the most prominent neurodegenerative disorders, particularly in elder persons over 65 age. It is characterized by progressive cognitive deterioration together with declining activities. Amyloid precursor protein (APP) cleaves at A-beta (Aβ) peptide by rate limiting factor of Beta-site APP cleaving enzyme (BACE-1) in amyloidogenic pathway. Elevated level of BACE-1 leads to the accumulation of an insoluble form of Aβ peptides (Senile Plaques), an important hallmark in the pathogenesis of Alzheimer disease. Five published inhibitors of BACE-1, thiazolidinediones, rosiglitazone, pioglitazone, Sc7 and tartaric acid are available with poor pharmacological properties and intolerable side effects. Therefore, a computational approach was undertaken to design novel inhibitors against human BACE-1. The crystal structure of human BACE-1 was retrieved from the protein data bank and optimized by applying OPLS force field in Maestro v9.2. An ASINEX database (115,000 ligands) was downloaded and compounds were prepared using LigPrep. The optimized ligand dataset was docked into the BACE-1 through sequential application of Glide HTVS, SP and XP methods that penalizes more stringently for minor steric classes subsequently. Finally, seven leads were reported and ranked based on XPGscore with better binding affinity and good pharmacological properties compared with existing inhibitors. Six leads were proposed for human BACE-1. Among the six, lead 1, with XPGscore -8.051Kcal/mol, would be intriguing for rational drug design against Alzheimer’s disease and would be highly encouraging for future Alzheimer’s therapy if tested in animal models

In silico identification of potential inhibitors for human aurora kinase b

Cell cycle progression through mitosis and meiosis involves regulation by serine/threonine kinases from the aurora family. Aurora kinase b (Aurkb) is mainly involved in the proper segregation of chromosomes during mitosis as well as meiosis. However, over expression of Aurkb leads to the unequal distribution of genetic information creating aneuploid cells, a hallmark of cancer. Thus, Aurkb can be used as an effective molecular target for computer-aided drug discovery against cancer. Existing Aurkb inhibitors are less efficient, hence an in silico work was carried out to identify novel potent inhibitors. Three published inhibitors azd1152, zm447439 and N-(4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy) quinazolin- 4-yl] amino} phenyl) benzamide were subjected to high throughput virtual screening of over 1 million entries from a ligand info meta database, to generate a 1161 compound library. The crystal structure was optimized and energy was minimized applying an OPLS force field in Maestro v9.0. Molecular docking using Glide was performed to predict the binding orientation of the prepared ligand molecule into a grid of 20*20*20 Å created around the centroid of the optimized human Aurkb protein. Nine lead molecules with good binding affinity with human Aurkb were identified. In silico pharmacokinetics study for these nine lead molecules has shown no ADME violation. Analysis of lead ‘1’- human Aurkb docking complex has revealed a XP Gscore of -10.20 kcal/mol with a highly stabilized hydrogen bond network with Asp218 and Ala157 and good Van der wall interactions. The docking complex coincides well with the native co- crystallized human Aurkb and inhibitor zm447439 complex. Thus, lead 1 would be highly useful for developing potential drug molecules for the treatment of cancer

In silico identification of potential inhibitors for human aurora kinase b

Cell cycle progression through mitosis and meiosis involves regulation by serine/threonine kinases from the aurora family. Aurora kinase b (Aurkb) is mainly involved in the proper segregation of chromosomes during mitosis as well as meiosis. However, over expression of Aurkb leads to the unequal distribution of genetic information creating aneuploid cells, a hallmark of cancer. Thus, Aurkb can be used as an effective molecular target for computer-aided drug discovery against cancer. Existing Aurkb inhibitors are less efficient, hence an in silico work was carried out to identify novel potent inhibitors. Three published inhibitors azd1152, zm447439 and N-(4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy) quinazolin- 4-yl] amino} phenyl) benzamide were subjected to high throughput virtual screening of over 1 million entries from a ligand info meta database, to generate a 1161 compound library. The crystal structure was optimized and energy was minimized applying an OPLS force field in Maestro v9.0. Molecular docking using Glide was performed to predict the binding orientation of the prepared ligand molecule into a grid of 20*20*20 Å created around the centroid of the optimized human Aurkb protein. Nine lead molecules with good binding affinity with human Aurkb were identified. In silico pharmacokinetics study for these nine lead molecules has shown no ADME violation. Analysis of lead ‘1’- human Aurkb docking complex has revealed a XP Gscore of -10.20 kcal/mol with a highly stabilized hydrogen bond network with Asp218 and Ala157 and good Van der wall interactions. The docking complex coincides well with the native co- crystallized human Aurkb and inhibitor zm447439 complex. Thus, lead 1 would be highly useful for developing potential drug molecules for the treatment of cancer

Envelope protein as molecular target for YFV (Yellow fever virus) drug discovery

Yellow fever (YF), a mosquito-borne viral haemorrhagic fever, is one of the most lethal viral diseases. Despite the availability of vaccines, yellow fever virus (YFV) strikes an estimated 2, 00,000 persons world-wide each year and causes 30,000 deaths approximately. There are no approved antiviral therapies for the treatment of YFV disease in humans. YFV 17D strain RNA genome is of 10,862 nucleotides, which encodes three structural proteins (C, PrM, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Identification of different protein functions facilitates a mechanistic understanding of YFV infection and opens novel means for drug development. Functional assignment of complete YFV proteome was done through support Vector machine (SVM). Significant functions of YFV Envelope (E) protein are Transmembrane, Aptamer-binding protein, Coat protein, Zinc-binding, Manganese-binding and Metal-binding etc. The E protein being non homologous to human and important in receptor binding, hemagglutination of erythrocytes at acidic pH, induction of the protective immune response, and involvement in an intraendosomal acid-catalyzed fusion step necessary for infection was selected as a potent molecular target against YFV drug discovery. 3D structure of target protein E protein is predicted using MODELLER9V6 and validated through PROCHECK analysis. The Binding site tool of Discovery Studio 2.0 was used to find sites all over protein. Heparin was identified as an important ligand against the molecular target and was docked to the functionally important binding site using LigandFit protocol. The YFV E protein -Heparin docking complex associated with strong hydrogen bonding with SER 483, GLN 443 and ALA 441 residues. The strong docking interaction may impede the infection causes due to association of YFV E protein and Core membrane. Further, the predicted model can be used as reference towards designing candidate drugs against YFV

Epigenetic studies in children at risk of stunting and their parents in India, Indonesia and Senegal : A UKRI GCRF Action Against Stunting Hub protocol paper

ASR provided research and organisational support within the Action Against Stunting Hub (AASH) epigenetics theme and drafted and revised the manuscript. MN led the AASH epigenetic theme in Senegal and oversees the implementation of the epigenetic protocol and contributed to the development of the protocol and critically revised the manuscript. RRK led the AASH epigenetic theme in India and oversaw the implementation of the epigenetic protocol, contributed to the development of the protocol and critically revised the manuscript. MKH led the AASH epigenetic theme in Indonesia and oversaw the implementation of the epigenetic protocol, contributed to the development of the protocol and critically revised the manuscript. DYD was responsible for monitoring evaluation and learning on the hub, critically reviewed the protocol and revised the manuscript. LFA managed the implementation of the study in India, critically reviewed the protocol and revised the manuscript. NLZ managed the implementation of the study in Indonesia, critically reviewed the protocol and revised the manuscript. AD managed the implementation of the study in Senegal, critically reviewed the protocol and revised the manuscript. DY, TCA and MN are epigenetic researchers in Indonesia, critically reviewed the protocol and reviewed the manuscript. MG, DS, SSV and MM are epigenetic researchers in India, critically reviewed the protocol and reviewed the manuscript. GWH advised on the statistical aspects of the protocol and the power calculation and reviewed the manuscript. UF is the AASH project lead in Indonesia, contributed to study design and coordination of the study and thematic linkages; supervised drafting of the manuscript. BF is the AASH project lead in Senegal, contributed to study design and coordination of the study and thematic linkages and supervised drafting of the manuscript. BK is the AASH project lead in India, contributed to study design and coordination of the study and thematic linkages and supervised drafting of the manuscript. PH is the AASH project deputy lead and epigenetic theme lead who designed the study, drafted and revised the manuscript, carried out the statistical calculations.Peer reviewe

In-silico analysis and identification of novel lead molecule for human IGFBP-4 involved in cardiovascular diseases

Cardiovascular disease is the major cause of disability and premature death throughout the world and contributes substantially to the escalating costs of health care. Insulin like growth factor binding protein 4 (IGFBP-4) mainly belongs to the family of IGFB protein. Over expression of IGFBP-4 leads to cardiovascular diseases namely stroke, acute myocardial infarction and heart failure. IGFBP-4 serves as an effective drug target against cardiovascular disease. Hence, ligand based virtual screening was persuaded in the present study to propose potential inhibitors of IGFBP-4. Two inhibitors (mainly from literature search) were selected to initiate high throughput virtual screening from small molecule databases namely, NCI, ChemBank, ChemPDB, AKos GmbH, Asinex Ltd and KEGG ligand. The structures listed through database search were docked with IGFBP-4 using virtual screening workflow of Maestro v9.2. Three leads that showed better binding affinity and good correlation with two published inhibitors were proposed as potential IGFBP-4 inhibitors. The three proposed leads showed good pharmacological properties in comparison to the two existing inhibitors. The analyses supported efficiency of three leads for next generation drug designing for cardiovascular diseases

In-silico analysis of human IGFBP-4 involved in cardiovascular diseases

Cardiovascular disease is the major cause of disability and premature death throughout the world and contributes substantially to the escalating costs of health care. Insulin like growth factor binding protein 4 (IGFBP-4) mainly belongs to the family of IGFB protein. Over expression of IGFBP-4 leads to cardiovascular diseases namely stroke, acute myocardial infarction and heart failure. IGFBP-4 serves as an effective drug target against cardiovascular disease. Hence, ligand based virtual screening was pursued in the present study to propose potential inhibitors of IGFBP-4. Two published inhibitors were selected to initiate high throughput virtual screening from small molecule databases namely, NCI, ChemBank, ChemPDB, AKos GmbH, Asinex Ltd and KEGG ligand. The structures listed through database search were docked with IGFBP-4 using virtual screening workflow of Maestro v9.2. Three leads that showed better binding affinity and good correlation than two published inhibitors were proposed as potential IGFBP-4 inhibitors. The three proposed leads showed good pharmacological properties in comparison to the two existing inhibitors for next generation drug designing against cardiovascular diseases

Ligand based virtual screening studies to design drug molecules for human PIN1 causing cardiovascular disease

PIN1 is a member of the cis/trans peptidyl-prolyl isomerase family which plays critical roles in cell-cycle regulation. Over expression of PIN1 in endothelial cells causes cardiovascular disease. The present study has focused on computational analysis to identify the potential inhibitors for PIN1. The human PIN1 crystal structure was retrieved from the protein data bank and prepared using protein preparation wizard of Maestro v9.2. Fourteen PIN1 inhibitors reported in recent literature were acquired and searched for structural analogs using Ligand.Info tool. 5675 PIN1 inhibitor analogs yielded were converted to 3D structures using LigPrep with constraints of ADME evaluation and toxicity assessments. The 3D ligand dataset was docked to PIN1 through docking protocol of Glide v5.7. Nine leads showing better binding affinity compared to fourteen published inhibitors were proposed as potential inhibitors of PIN1. The Lead 1 (2-(2-hydroxy-5-methoxy-pheny)-1h-benzoimidazole-5-carboxamidine) showed a docking score of -7.543 kcal/mol with strong hydrogen bond network with active site residues such as Arg-74, Tyr-92 and Glu-110 and good van der Waals interaction. Therefore, Lead 1 is proposed as a promising lead for developing potential drug molecules for cardiovascular disease therapy

In silico designing of activator for human IGF2 protein for effective cardiovascular disease therapeutics

Insulin like growth factor-II (IGF2) is a member of IGF family, the main role of IGF2 is as a growth hormone during gestation or fetal development. Ischematic stroke, atherosclerosis and pathological cardiac hypertrophy are associated with low circulating levels of IGF2. 5-aza-2’-deoxycytidine increases the activity of IGF2, due to high toxicity of 5aza2’deoxycytidine, some silenced genes are also expressed that cause various cancer diseases. In the present study an in silico approach was used to design the potential activator for IGF2 without side effects to treat cardiovascular diseases. Ligand binding sites were predicted using CASTp for drug target. 361 ligand analogs for 5-aza-2’-deoxycytidine were identified through virtual screening from Ligand.Info database. Docking studies were performed using Schrodinger software (2010) generated 13 lead agonists for human IGF2. Docking complexes of 13 lead agonists and 5aza2’deoxycytidine with IGF2 were compared and four leads with better affinity, ADME properties and lower XPGscore than 5-aza-2’-deoxycytidine were proposed as potential activators. Lead‘1’ (mizoribine), the best ranked activator (XPG score -7.181) having good binding affinity, could be a better drug for cardiovascular diseases and it is forming three hydrogen bonds, two bonds with Thr-58 and one bond with Cys-60, and van der Waal interactions with the binding site residues of IGF2 such as Leu-13, Leu-17 Ile-42, Val-43, Cys-46, Leu-56 and Try -59. Mizoribine decreases the proliferation of vascular smooth muscle cells and the elevated levels of human IGF2 helps in cardiovascular therapies