Pharmacophore Mapping Approach for Drug Target Identification: A Chemical Synthesis and in Silico Study on Novel Thiadiazole Compounds

Abstract

Introduction: Compounds containing thiadiazole moiety are cognized to possess with variety of clinical and therapeutic activity. Finding a suitable drug target for newly synthesized compounds remain a major bottle neck in current high throughout medicinal chemistry era. Aim:To effectively synthesize di substituted thiadiazole com pounds and demonstrate drug target identification using an in silico pharmacophore probing approach. Moreover, we also aim to validate the suitability of identified drug target. Materials and Methods:A costeffective and environmental friendly chemical synthesis scheme for production of di substituted thiadiazole compounds was employed. Target identification was conducted by Pharmmapper software. Validation was accomplished by performing molecular docking and further Molecular Hydrophobic Potential (MHP) analysis.Results: Pharmacophore probing base approach identified hepatocyte growth factor receptor (cMet) as a suitable biological target for newly synthesized compounds. Binding free energy values indicate that compound 4b, 4e, 4g and 4h has tremendous potential to be further used as lead compound to design selective inhibitors of cMet receptor. MHP data from current study supports the possibility that hydrophobic contacts might act as major factor stabilizing thiadiazole cMet complex. Moreover, in silico observations of current study are in absolute accordance with previously described in vitro and crystallographic analysis. Conclusion:We demonstrate that thiadiazole compounds synthesized in current investigation has high potential to act in modulation of hepatocyte growth factor receptor (cMet) activity and thereby act as putative therapeutic agent in cancer therapy.[Table/ Fig-1]: Schematic representation of methodology adopted in synthesis of novel thiadiazole derivatives in current study.

Preparation of a steroid-oxazole-1,2′-[1,3]oxazete] derivative: biological and theoretical evaluation of its interaction with a kinase protein (CK2)

“…There are some studies that indicate that the pharmacophore is the three-dimensional orientation adopted by the functional groups of a molecule to be able to interact with some proteins [44]. This pharmacophore model can furnish a new insight to design novel molecules that can enhance or inhibit the function of the target and will be useful in drug discovery strategies.…”

Computational prediction and in vitro validation of VEGFR1 as a novel protein target for 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…The validated model was subjected to energy minimization using NOMADRef server 61 with conjugate gradient method and chosen for further study. For human VEGFR1 (hVEGFR1), crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1(PDB ID: 1RV6) 31 downloaded from Protein Data Bank (PDB) 22 was used for further study.…”

“…Identification of novel protein targets and their validation is one of the key steps in the discovery and development of novel pathways in several diseases. In general, identification of novel potential targets for a chemical compound involves extensive proteomic approach involving comparison of the protein expression profiles in a given cell/ tissue in the presence/absence of the given chemical compound 22 . There are certain unavoidable shortcomings in predicting the novel targets for new chemicals or ligands due to time-consuming and expensive nature of the experimental methods to predict.…”

“…There are certain unavoidable shortcomings in predicting the novel targets for new chemicals or ligands due to time-consuming and expensive nature of the experimental methods to predict. Several novel computational methods and algorithms have emerged in recent years to predict possible biological targets for ligands 22–27 . A previous study reported diverse proteins such as metallopeptidases 8 and 3, oxidosqualene cyclase and myeloperoxidase as theoretical targets for TCDD using Bioinformatics approach 28 .…”

Modern Paradigm Towards Potential Target Identification for Antiviral (SARS-nCoV-2) and Anticancer Lipopeptides: A Pharmacophore-Based Approach

“…These techniques are based upon comparative studies on protein expression profiling concerning the presence and absence of a given molecule for a particular cell or tissue. Such methods are not much successful in the discovery of target proteins because these are time consuming and laborious 18 . In the case of large molecule natural compounds, the task is even more challenging to execute and incurs huge wastage of chemicals and time 19 .…”