Novel Non-Peptide Inhibitors against SmCL1 of Schistosoma mansoni: In Silico Elucidation, Implications and Evaluation via Knowledge Based Drug Discovery

Abstract

Schistosomiasis is a major endemic disease known for excessive mortality and morbidity in developing countries. Because praziquantel is the only drug available for its treatment, the risk of drug resistance emphasizes the need to discover new drugs for this disease. Cathepsin SmCL1 is the critical target for drug design due to its essential role in the digestion of host proteins for growth and development of Schistosoma mansoni. Inhibiting the function of SmCL1 could control the wide spread of infections caused by S. mansoni in humans. With this objective, a homology modeling approach was used to obtain theoretical three-dimensional (3D) structure of SmCL1. In order to find the potential inhibitors of SmCL1, a plethora of in silico techniques were employed to screen non-peptide inhibitors against SmCL1 via structure-based drug discovery protocol. Receiver operating characteristic (ROC) curve analysis and molecular dynamics (MD) simulation were performed on the results of docked protein-ligand complexes to identify top ranking molecules against the modelled 3D structure of SmCL1. MD simulation results suggest the phytochemical Simalikalactone-D as a potential lead against SmCL1, whose pharmacophore model may be useful for future screening of potential drug molecules. To conclude, this is the first report to discuss the virtual screening of non-peptide inhibitors against SmCL1 of S. mansoni, with significant therapeutic potential. Results presented herein provide a valuable contribution to identify the significant leads and further derivatize them to suitable drug candidates for antischistosomal therapy.

Molecular Docking Study of Gingkgo biloba Compounds as Potential Inhibitors of SARS-CoV-2

“…Thus, the value of binding energy can be used to predict the ability of a compound to inhibit proteins. [22] Jin et al reported that the threshold of binding energy is ≤ -5.0 kcal/mol, so values less than -5.0 kcal/mol are considered to have strong binding effect with the key proteins. [23] A molecular docking study conducted by Hussain et al showed that the binding sites of TMPRSS2 were amino acid residues of Gln276, Arg413, Glu299, and Thr387.…”

Identifikasi Senyawa Aktif Pala (Myristica fragrans) sebagai Terapi Komplementer Antihipertensi melalui Penghambatan Reseptor ACE: Sebuah Studi Penambatan Molekuler

“…Oleh karena itu, semakin rendah nilai G (semakin besar nilai negatif), semakin tinggi energi ikat antara ligan dan protein target [20]. Selain itu, Zafar et al [21] menyatakan bahwa terdapat hubungan linier antara nilai konstanta penghambatan (Ki) dengan nilai energi ikatan. Dengan demikian, nilai energi ikatan dapat digunakan untuk memprediksi kemampuan suatu senyawa dalam menghambat protein.…”

Formal concept analysis for knowledge discovery from biological data

“…Hence, for reliable and safer drug therapy, discovery and optimisation of non-peptide inhibitors/drugs is necessary [28]. Moreover, in a recent in silico identifications of the drug molecules for Cathepsin L (SmCL1) of the organism, Schistosoma mansoni responsible for the disease schistosomiasis, it was revealed that the non-peptide molecules could be better drug molecules as compared to peptide drugs molecules [30]. The list of popularly used software tool based on FCA is shown in Table 1.…”