Structure-Based Virtual Screening of Furan-1,3,4-Oxadiazole Tethered N-phenylacetamide Derivatives as Novel Class of hTYR and hTYRP1 Inhibitors

Ali Irfan; Shah Faisal; Sajjad Ahmad; Sami A Al-Hussain; Sadia Javed; Ameer Fawad Zahoor; Bushra Parveen; Magdi E A Zaki

doi:10.3390/ph16030344

Structure-Based Virtual Screening of Furan-1,3,4-Oxadiazole Tethered N-phenylacetamide Derivatives as Novel Class of hTYR and hTYRP1 Inhibitors

Pharmaceuticals (Basel). 2023 Feb 23;16(3):344. doi: 10.3390/ph16030344.

Authors

Ali Irfan¹, Shah Faisal², Sajjad Ahmad³, Sami A Al-Hussain⁴, Sadia Javed⁵, Ameer Fawad Zahoor¹, Bushra Parveen¹, Magdi E A Zaki⁴

Affiliations

¹ Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan.
² Department of Chemistry, Islamia College University Peshawar, Peshawar 25120, Pakistan.
³ Department of Health and Biological Sciences, Abasyn University, Peshawar 25000, Pakistan.
⁴ Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia.
⁵ Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan.

Abstract

Human tyrosinase (hTYR) is a key and rate-limiting enzyme along with human tyrosinase-related protein-1 (hTYRP1), which are among the most prominent targets of inhibiting hyper pigmentation and melanoma skin cancer. In the current in-silico computer-aided drug design (CADD) study, the structure-based screening of sixteen furan-1,3,4-oxadiazole tethered N-phenylacetamide structural motifs BF1-BF16 was carried out to assess their potential as hTYR and hTYRP1 inhibitors. The results revealed that the structural motifs BF1-BF16 showed higher binding affinities towards hTYR and hTYRP1 than the standard inhibitor kojic acid. The most bioactive lead furan-1,3,4-oxadiazoles BF4 and BF5 displayed stronger binding in affinities (-11.50 kcal/mol and -13.30 kcal/mol) than the standard drug kojic acid against hTYRP1 and hTYR enzymes, respectively. These were further confirmed by MM-GBSA and MM-PBSA binding energy computations. The stability studies involving the molecular dynamics simulations also provided stability insights into the binding of these compounds with the target enzymes, wherein it was found that they remain stable in the active sites during the 100 ns virtual simulation time. Moreover, the ADMET, as well as the medicinal properties of these novel furan-1,3,4-oxadiazole tethered N-phenylacetamide structural hybrids, also showed a good prospect. The excellent in-silico profiling of furan-1,3,4--oxadiazole structural motifs BF4 and BF5 provide a hypothetical gateway to use these compounds as potential hTYRP1 and hTYR inhibitors against melanogenesis.

Keywords: MD simulations; furan-1,3,4-oxadiazole; hTYR; hTYRP1; melanogenesis; molecular docking.

Grants and funding

Research Group no. RG 21-09-77./The authors thank the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University for funding this work through Research Group no. RG 21-09-77.