Browsing by Author "Weako, Jackson"

Now showing 1 - 3 of 3

Citation - WoS: 13
Citation - Scopus: 19
Examining the Stability of Binding Modes of the Co-Crystallized Inhibitors of Human Hdac8 by Molecular Dynamics Simulation
(Taylor & Francis Inc, 2019) Uba, Abdullahi Ibrahim; Yelekçi, Kemal; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; Yelekçi, Kemal
Histone deacetylase (HDAC) 8 has been implicated as a potential therapeutic target in a variety of cancers neurodegenerative disorders metabolic dysregulation and autoimmune and inflammatory diseases. Several nonselective HDAC inhibitors have been co-crystallized with HDAC8. Molecular dynamics (MD) studies may yield valuable information on the structural stabilities of the complexes over time as determined by various pharmacophore features of the co-crystallized inhibitors. Here using 11 unmodified X-ray crystal structures of human HDAC8 (complexes) structure-based pharmacophore models were built and clustered based on distance - a function of the number of common pharmacophore features and the root-mean-squared displacement between the matching features. Based on this information a total of seven complexes (1T64 1W22 3RQD 3SFF 3F0R 5VI6 and 5FCW) were submitted to unrestrained 50 ns-MD simulations using nanoscale MD (NAMD) software. 1T64 (HDAC8 in complex with TSA) was found to show the highest stability over time presumably because of the TSA's ability to span HDAC8 catalytic channel and form a strong ionic interaction with zinc metal ion. Other stable complexes were 1W22 3SFF 3F0R and 5FCW. However 3RQD and 5VI6 showed relative instability over 50 ns time period. This may be attributed to bulkiness of the capping groups of both largazole thiol and trapoxin A making them unable to fit well into the active site of HDAC8. They rather formed steric clashes with residues on loop regions near the entrance to the channel. Thus 1T64 and similar crystal structures may be good candidates for HDAC8 structural dynamics studies and inhibitor design. Communicated by Ramaswamy H. Sarma
Citation - WoS: 16
Citation - Scopus: 18
Identification of Potential Inhibitors of Human Methionine Aminopeptidase (type Ii) for Cancer Therapy: Structure-Based Virtual Screening, Admet Prediction and Molecular Dynamics Studies
(Elsevier, 2020) Weako, Jackson; Yelekçi, Kemal; Uba, Abdullahi Ibrahim; Keskin, Özlem; Gürsoy, Attila; Yelekçi, Kemal
Methionine Aminopeptidases MetAPs are divalent-cofactor dependent enzymes that are responsible for the cleavage of the initiator Methionine from the nascent polypeptides. MetAPs are classified into two isoforms: namely, MetAP1 and MetAP2. Several studies have revealed that MetAP2 is upregulated in various cancers, and its inhibition has shown to suppress abnormal or excessive blood vessel formation and tumor growth in model organisms. Clinical studies show that the natural product fumagillin, and its analogs are potential inhibitors of MetAP2. However, due to their poor pharmacokinetic properties and neurotoxicities in clinical studies, their further developments have received a great setback. Here, we apply structure-based virtual screening and molecular dynamics methods to identify a new class of potential inhibitors for MetAP2. We screened Otava's Chemical Library, which consists of about 3 200 000 tangible-chemical compounds, and meticulously selected the top 10 of these compounds based on their inhibitory potentials against MetAP2. The top hit compounds subjected to ADMET predictor using 3 independent ADMET prediction programs, were found to be drug-like. To examine the stability of ligand binding mode, and efficacy, the unbound form of MetAP2, its complexes with fumagillin, spiroepoxytriazole, and the best promising compounds compound-3369841 and compound-3368818 were submitted to 100 ns molecular dynamics simulation. Like fumagillin, spiroepoxytriazole, and both compound-3369841 and compound-3368818 showed stable binding mode over time during the simulations. Taken together, these uninherited-fumagillin compounds may serve as new class of inhibitors or provide scaffolds for further optimization towards the design of more potent MetAP2 inhibitors -development of such inhibitors would be essential strategy against various cancer types.
In Silico Screening of Tangible-Potential Inhibitor of Methionine Aminopeptidase 2 for the Treatment of Cancer
(Kadir Has Üniversitesi, 2017) Weako, Jackson; Yelekçi, Kemal; Yelekçi, Kemal
Methionine Aminopeptidases (MetAPs) are divalent-cofactor dependent enzymes that are responsible for cleaving the initiator Methionine from the newly synthesized polypeptides. These metalloproteases are classified into two distinct isoforms- MetAP1 and MetAP2. The MetAP2 isoform is upregulated in many cancerous cells. A selective inhibition of MetAP2 is an effective means of suppressing vascularization and limiting both the size and metastasis of solid tumors in a model organism. A selective and potent inhibitor of MetAP2 is the natural product – fumagillin. Fumagillin and its semi-synthetic analogs have been shown as promising candidates in various clinical trials for treating cancer and in rent time for treating obesity. However their further developments have received a great setback due to their poor pharmacokinetic properties and neurotoxicities in clinical studies. Here in an effort to find potential inhibitors of MetAP2 in-silico Screening and Molecular Modelling were applied to generate a new class of inhibitors. The OTAVA's Chemical Library was screened and ten best compounds were selected based on their structural physicochemical properties and inhibitory potentials against MetAP2. PyRx AutoDock 4.2 and Accelrys (BiOViA Discovery Studio version 2016) were deployed to obtain these potential inhibitors. Utilizing OTAVA's Chemical Library 130 potential drug candidates were selected based on a threshold of -9.0Kcal/mole using PyRx. in order to re-evaluate and validate these 130 inhibitors AutoDock 4.2 was employed to dock these selected candidates. A total of 71 potential candidates were selected based on AutoDock result. Further analysis of their inhibition constants and Gibbs free energies led to the ten best potential candidates. Accelrys (BiOViA Discovery Studio version 2016) was used to identify the positions of these candidates in the active site of MetAP2. Discovery Studio's ADMET protocols was used to determine the pharmacokinetics properties of these candidates. it is anticipated herein that these candidates will serve as a new class of inhibitors and/or lead compounds for MetAP2.