PMID- 35812153 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 1319-0164 (Print) IS - 2213-7475 (Electronic) IS - 1319-0164 (Linking) VI - 30 IP - 6 DP - 2022 Jun TI - Identification of potent aldose reductase inhibitors as antidiabetic (Anti-hyperglycemic) agents using QSAR based virtual Screening, molecular Docking, MD simulation and MMGBSA approaches. PG - 693-710 LID - 10.1016/j.jsps.2022.04.003 [doi] AB - The aldose reductase (AR) enzyme is an important target enzyme in the development of therapeutics against hyperglycaemia induced health complications such as retinopathy, etc. In the present study, a quantitative structure activity relationship (QSAR) evaluation of a dataset of 226 reported AR inhibitor (ARi) molecules is performed using a genetic algorithm - multi linear regression (GA-MLR) technique. Multi-criteria decision making (MCDM) analysis furnished two five variables based QSAR models with acceptably high performance reflected in various statistical parameters such as, R(2) = 0.79-0.80, Q(2) (LOO) = 0.78-0.79, Q(2) (LMO) = 0.78-0.79. The QSAR model analysis revealed some of the molecular features that play crucial role in deciding inhibitory potency of the molecule against AR such as; hydrophobic Nitrogen within 2 A of the center of mass of the molecule, non-ring Carbon separated by three and four bonds from hydrogen bond donor atoms, number of sp2 hybridized Oxygen separated by four bonds from sp2 hybridized Carbon atoms, etc. 14 in silico generated hits, using a compound 18 (a most potent ARi from present dataset with pIC(50) = 8.04 M) as a template, on QSAR based virtual screening (QSAR-VS) furnished a scaffold 5 with better ARi activity (pIC(50) = 8.05 M) than template compound 18. Furthermore, molecular docking of compound 18 (Docking Score = -7.91 kcal/mol) and scaffold 5 (Docking Score = -8.08 kcal/mol) against AR, divulged that they both occupy the specific pocket(s) in AR receptor binding sites through hydrogen bonding and hydrophobic interactions. Molecular dynamic simulation (MDS) and MMGBSA studies right back the docking results by revealing the fact that binding site residues interact with scaffold 5 and compound 18 to produce a stable complex similar to co-crystallized ligand's conformation. The QSAR analysis, molecular docking, and MDS results are all in agreement and complementary. QSAR-VS successfully identified a more potent novel ARi and can be used in the development of therapeutic agents to treat diabetes. CI - (c) 2022 The Author(s). FAU - Bakal, Ravindra L AU - Bakal RL AD - Department of Medicinal Chemistry, Dr. Rajendra Gode Institute of Pharmacy, University-Mardi Road, Amravati, Maharashtra, India. FAU - Jawarkar, Rahul D AU - Jawarkar RD AD - Department of Medicinal Chemistry, Dr. Rajendra Gode Institute of Pharmacy, University-Mardi Road, Amravati, Maharashtra, India. FAU - Manwar, J V AU - Manwar JV AD - Department of Medicinal Chemistry and Pharmacognosy, Dr. Rajendra Gode College of Pharmacy, University-Mardi Road, Amravati, Maharashtra, India. FAU - Jaiswal, Minal S AU - Jaiswal MS AD - Department of Medicinal Chemistry and Pharmacognosy, Dr. Rajendra Gode College of Pharmacy, University-Mardi Road, Amravati, Maharashtra, India. FAU - Ghosh, Arabinda AU - Ghosh A AD - Microbiology Division, Department of Botany, Gauhati University, Guwahati, Assam 781014, India. FAU - Gandhi, Ajaykumar AU - Gandhi A AD - Department of Chemistry, Government College of Arts and Science, Aurangabad, Maharashtra 431 004, India. FAU - Zaki, Magdi E A AU - Zaki MEA AD - Department of Chemistry, Faculty of Science, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh 13318, Saudi Arabia. FAU - Al-Hussain, Sami AU - Al-Hussain S AD - Department of Chemistry, Faculty of Science, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh 13318, Saudi Arabia. FAU - Samad, Abdul AU - Samad A AD - Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq. FAU - Masand, Vijay H AU - Masand VH AD - Department of Chemistry, Vidyabharti Mahavidyalaya, Camp Road, Amravati, Maharashtra, India. FAU - Mukerjee, Nobendu AU - Mukerjee N AD - Department of Microbiology, Ramakrishna Mission Vivekananda Centenary College, West Bengal 700118, Kolkata, India. AD - Department of Health Sciences, Novel Global Community Educational Foundation, Australia. FAU - Nasir Abbas Bukhari, Syed AU - Nasir Abbas Bukhari S AD - Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, Sakaka, 2014, Saudi Arabia. FAU - Sharma, Praveen AU - Sharma P AD - Department of Pharmaceutics, Vinayaka College of Pharmacy, Hathod, Indore, Madhyapradesh, India. FAU - Lewaa, Israa AU - Lewaa I AD - Department of Business Administration, Faculty of Business Administration, Economics and Political Science, British University in Egypt, Elsherouk City, Cairo 11837, Egypt. LA - eng PT - Journal Article DEP - 20220407 PL - Saudi Arabia TA - Saudi Pharm J JT - Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society JID - 9705695 PMC - PMC9257878 OTO - NOTNLM OT - Aldose reductase OT - Antidiabetic OT - Ari, Aldose Reductase Inhibitors OT - CADD, Computer Aided Drug Designing OT - CCC, Concordance Correlation Coefficient OT - GA, Genetic Algorithm OT - GA-MLR OT - H_ringN_2B, H_ringN_2B represents a combination of ring nitrogen and hydrogen separated by within 2 bonds OT - MD, Molecular Dynamic OT - MDS OT - MLR, Multiple Linear Regression OT - MMGBSA, Molecular mechanics generalized born surface area OT - Minus_don_3B, Occurrence of a donor within three bonds from a negatively charged atom OT - Molecular Docking OT - OECD, Organization for Economic Co-operation and Development OT - OLS, Ordinary Least Square OT - QSAR OT - QSAR, Quantitative Structure-Activity Relationship OT - QSAR, Quantitative structure activity Relationship OT - QSARINS, QSAR Insubria OT - SMILES, Simplified Molecular, Input Line-Entry System OT - Virtual screening OT - allminus_SASA, Solvent Accessible surface area of the all negatively charged atoms OT - com_Nhyd_2A, presence of hydrophobic nitrogen within 2A of the center of mass OT - com_ringCminus_2A, Encodes information on the number of negatively charged ring Carbon atoms within 2A from the center of mass of the molecule OT - don_notringC_4B, Occurrence of the non-ring carbon atom within four bonds from the donor OT - don_ringC_6Ac, Occurrence of the partially charged ring carbon atoms within 6A of the donor OT - fsp2Osp2C4B, the frequency of occurrence of a sp2 hybridized carbon atom exactly four bonds from a sp2 hybridized oxygen atom COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/07/12 06:00 MHDA- 2022/07/12 06:01 PMCR- 2022/04/07 CRDT- 2022/07/11 03:43 PHST- 2021/10/23 00:00 [received] PHST- 2022/04/01 00:00 [accepted] PHST- 2022/07/11 03:43 [entrez] PHST- 2022/07/12 06:00 [pubmed] PHST- 2022/07/12 06:01 [medline] PHST- 2022/04/07 00:00 [pmc-release] AID - S1319-0164(22)00102-5 [pii] AID - 10.1016/j.jsps.2022.04.003 [doi] PST - ppublish SO - Saudi Pharm J. 2022 Jun;30(6):693-710. doi: 10.1016/j.jsps.2022.04.003. Epub 2022 Apr 7.