Computational Approaches for the Design of Novel Anticancer Compounds Based on Pyrazolo[3,4-d]pyrimidine Derivatives as TRAP1 Inhibitor

Amena Ali; Magda H Abdellattif; Abuzer Ali; Ola AbuAli; Mohd Shahbaaz; Mohamed Jawed Ahsan; Mostafa A Hussien

doi:10.3390/molecules26195932

Computational Approaches for the Design of Novel Anticancer Compounds Based on Pyrazolo[3,4-d]pyrimidine Derivatives as TRAP1 Inhibitor

Molecules. 2021 Sep 30;26(19):5932. doi: 10.3390/molecules26195932.

Authors

Amena Ali¹, Magda H Abdellattif², Abuzer Ali³, Ola AbuAli², Mohd Shahbaaz^{4

5}, Mohamed Jawed Ahsan⁶, Mostafa A Hussien^{7

8}

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
² Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
³ Department of Pharmacognosy, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁴ South African Medical Research Council Bioinformatics Institute, University of Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa.
⁵ Laboratory of Computational Modelling of Drugs, South Ural State University, 76 Lenin Prospects, 454080 Chelyabinsk, Russia.
⁶ Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Ambabari Circle, Jaipur 302039, India.
⁷ Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia.
⁸ Department of Chemistry, Faculty of Science, Port Said University, Port Said 42521, Egypt.

Abstract

In the present in-silico study, various computational techniques were applied to determine potent compounds against TRAP1 kinase. The pharmacophore hypothesis DHHRR_1 consists of important features required for activity. The 3D QSAR study showed a statistically significant model with R² = 0.96 and Q² = 0.57. Leave one out (LOO) cross-validation (R² CV = 0.58) was used to validate the QSAR model. The molecular docking study showed maximum XP docking scores (-11.265, -10.532, -10.422, -10.827, -10.753 kcal/mol) for potent pyrazole analogs (42, 46, 49, 56, 43), respectively, with significant interactions with amino acid residues (ASP 594, CYS 532, PHE 583, SER 536) against TRAP1 kinase receptors (PDB ID: 5Y3N). Furthermore, the docking results were validated using the 100 ns MD simulations performed for the selected five docked complexes. The selected inhibitors showed relatively higher binding affinities than the TRAP1 inhibitor molecules present in the literature. The ZINC database was used for a virtual screening study that screened ZINC05297837, ZINC05434822, and ZINC72286418, which showed similar binding interactions to those shown by potent ligands. Absorption, distribution, metabolism, and excretion (ADME) analysis showed noticeable results. The results of the study may be helpful for the further development of potent TRAP1 inhibitors.

Keywords: 3D-QSAR pharmacophore modeling; TRAP1; TRAP1 kinase; molecular dynamics simulations; virtual screening.

MeSH terms

Antineoplastic Agents / chemistry*
Computer Simulation
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Humans
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Neoplasms / drug therapy*
Pyrimidines / chemistry*
Quantitative Structure-Activity Relationship

Substances

Antineoplastic Agents
HSP90 Heat-Shock Proteins
Ligands
Pyrimidines
TRAP1 protein, human