DOI 10.1007/s13233-022-0071-3 www.springer.com/13233 pISSN 1598-5032 eISSN 2092-7673 Macromolecular Research Article Macromol. Res. 1 © The Polymer Society of Korea and Springer 2022 Chemometric Study, Homology Modeling of G Protein-Coupled Bile Acids Receptor (GPBAR_HUMAN) of Type-2 Diabetes Mellitus, Virtual Screening Evaluation, Drug-Likeness and ADME Prediction for Newly Designed Compounds Abstract: Chemometric validation of the reported experimental activities of nico- tinamide and carboxamide analogues against diabetes were determined via quanti- tative structure-activity relationship (QSAR) model using ATS1p, AATSC1m, nHother and RDF80p descriptors. Meanwhile, GPBAR_HUMAN with a UniProtKB code (Q8TDU6) for G protein-coupled bile acid was known as a potential drug target in human TGR5 of Type 2 diabetes mellitus (T2DM) whose crystal structure wasn’t found in the Pro- tein Data Bank. With the aid of in-Silico approach via homology modeling helps to build a 3D protein (target) model with the availability of GPBAR_HUMAN sequence data. The swiss-Model online workspace was used to model the GPBAR_HUMAN receptor using the Cryo-EM structure of the INT-777-bound GPBAR-Gs complex with PDB code (7CFN) as a potential template. The built receptor was evaluated, val- idated, and used as a target protein for molecular docking simulation of some potent nicotinamide and carboxamide series. The virtual screening studies via molecular docking revealed the binding pockets, binding modes and poses of the GPBAR_HU- MAN receptor with some prominent anti-diabetic agents. Analysis of these interac- tions led to computational design via a structure-based approach of new potent anti-diabetic compounds with significant binding scores and better interactions with the GPBAR_HUMAN receptor. Validation of the designed compounds via Drug-likeness and ADME prediction confirmed that these compounds are orally bioavailable with a good lipophilicity index for lipid environments and show zero violation to the drug assessment rules in order to be considered as drug candidates. Therefore, in-vitro and an in-vivo test to transform these findings into potent therapeutics are strongly recommended. Keywords: diabetes, binding score, drug-likeness, homology modelling, QSAR. 1. Introduction Diabetes is known as one of the global epidemic illness which occur as a result of the body not being able to produce sufficient insulin. This hormone is created by some special cells known as Beta cells located in the pancreas. However, poor cellular intake compromises the efficiency of these cells which led to overbur- dened of the cell and eventually wear out. Consequently, excess glucose builds up in the blood due to poor insulin response or low insulin level which then result in diabetes mellitus. 1 Conse- quently, an increase of 5% untimely mortality has been reported to take place from 2016 to 2000 while cases of 1.5 million peo- ple in 2019 have been recorded death as a result of epidemic disease. 2 A Type-2 diabetes mellitus (T2DM) is referred to as ‘‘Non- Insulin Dependent Diabetes Mellitus (NIDDM)’’ occurs when insulin is being resisted by the body. 1,3 Hence, a metabolic ail- ment with an extremely high level of glucose is mixed in the blood and spills into the urine. Some of the notable symptoms associated with the disease are dramatic weight loss, poorly healing wound, fatigue and weakness, vomiting and nausea, frequent urination, blurred vision and irritation of the eyes increase appetite and excessive thirst and itching of the skin. With these effects, numerous drugs to combat this disease have been developed. 1 However, reposts have shown that patients battling with diseases are finding it difficult to get adequate and full control without any/fewer side effects using these drugs as a potential treatment. In recent times, a potential drug target ‘‘human TGR5’’ of Type 2 diabetes mellitus is a new class of G protein-coupled Bile Acids which was newly discovered. Initially, Farnesoid X-receptor (FXR) was the first recognized target initiated by Bile Acids (Bas). A report has shown that a moderate level of TGR5 is mostly located in the spleen, placenta and intestine while the highest level is Shola Elijah Adeniji* ,1 Abduljelil Ajala 1 David Ebuka Arthur 2 Mustapha Abdullahi 3 Omole Isaac Areguamen 4 Chemistry Department, Ahmadu Bello University, Zaria, Nigeria Pure and applied Chemistry Department, University of Maiduguri, Maiduguri, Nigeria Chemistry Department, Kaduna State University, Kaduna, Nigeria Applied Chemistry Department, Federal University Dutsinma Katsina, Nigeria Received December 30, 2021/Revised March 19, 2022/Accepted April 28, 2022 *Corresponding Author: Shola Elijah Adeniji (shola4343@gmail.com)