Model Optimization and In Silico Analysis of Potential Dipeptidyl Peptidase IV Antagonists from GC-MS Identified Compounds in Nauclea latifolia Leaf Extracts

Abstract

Dipeptidyl peptidase IV (DPP-IV) is a pharmacotherapeutic target in type 2 diabetes. Inhibitors of this enzyme constitute a new class of drugs used in the treatment and management of type 2 diabetes. In this study, phytocompounds in Nauclea latifolia (NL) leaf extracts, identified using gas chromatography–mass spectroscopy (GC-MS), were tested for potential antagonists of DPP-IV via in silico techniques. Phytocompounds present in N. latifolia aqueous (NLA) and ethanol (NLE) leaf extracts were identified using GC–MS. DPP-IV model optimization and molecular docking of the identified compounds/standard inhibitors in the binding pocket was simulated. Drug-likeness, pharmacokinetic and pharmacodynamic properties of promising docked leads were also predicted. Results showed the presence of 50 phytocompounds in NL extracts of which only 2-O-p-methylphenyl-1-thio-β-d-glucoside, 3-tosylsedoheptulose, 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol and vitamin E exhibited comparable or better binding iGEMDOCK and AutoDock Vina scores than the clinically prescribed standards. These four compounds exhibited promising drug-likeness as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties suggesting their candidature as novel leads for developing DPP-IV inhibitors.

α-Amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory effects of Melicope latifolia bark extracts and identification of bioactive constituents using in vitro and in silico approaches

“…The binding affinity of compound 3 with DPP-4 was lower than those reported for 1,2,4-benzenetriol, dodecanoic acid, and benzoic acid (Iheagwam et al. 2019b ). Identical amino acid interactions have also been observed with other potent natural DPP-4 inhibitors such as flavones and resveratrol (Jha and Bhadoriya 2018 ).…”

“…Tyr666 and Tyr662 were located near the catalytic triad (Ser630, Asn710, and His740) of the DPP-4 enzyme, therefore, interactions with Tyr666 and Tyr662 may interfere with the catalytic actions of the enzyme. The binding affinity of compound 3 with DPP-4 was lower than those reported for 1,2,4benzenetriol, dodecanoic acid, and benzoic acid (Iheagwam et al 2019b). Identical amino acid interactions have also been observed with other potent natural DPP-4 inhibitors such as flavones and resveratrol (Jha and Bhadoriya 2018).…”

Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants

“…Upon energy minimisation of the modelled helicase, a root-mean-square deviation (RMSD) score of 0.387 and 0.588 Å was observed when superimposed with the modelled helicase and 5wwp, respectively ( Figure S2 ). This observation suggests the homology model has a high similarity and structural orderliness with the template as corroborated by studies on TMPRSS2 and dipeptidyl peptidase 4 [ 17 , 36 ]. The model also had good stereochemical quality as conferred by the Ramachandran plot with reduced noise as shown in Table S3 with a 3D verification score of 94.7% and quality factor of 88.14% further corroborating the reliability of the model (Figures S3 and S4 , respectively).…”

“…Lipinski's rule of 5 and its variants are used to predict if small chemical compounds detected as pharmaceutical leads are orally active [ 69 – 72 ]. 3-Galloylcatechin could be ascertained to be orally active based on a consensus that only one parameter is violated in Lipinski's RO5 [ 36 ]. The druglikeness failure exhibited by the compounds is not surprising as NPs have been reported to fail Lipinski's druglikeness test, which is attributed to their mechanism of absorption [ 73 ].…”

“…The protein structures of SARS-CoV-2 papain-like protease (PLpro), main/3-chymotrypsin-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), helicase, 2-O-methyltransferase (2OMT), spike receptor-binding domain (S-RBD), human angiotensin-converting enzyme 2 (ACE2), and human type-II transmembrane serine protease (TMPRSS2) with PDB codes 6w9c, 6lu7, 6m71, 6w4h, 6m17.E, 6m17.B, and 5ce1, respectively, were retrieved from protein data bank ( http://www.rcsb.org ). Experimental SARS-CoV-2 helicase structure is yet to be deposited in the protein data bank; hence, a homology structure was modelled as described by Iheagwam and Ogunlana [ 36 ]. Briefly, SARS-CoV-2 helicase sequence was acquired from UniProt ( http://www.uniprot.org ) via the UniProt identifier (P0DTD1) with a feature identifier (PRO_0000449630).…”