New D2R partial agonist candidates: an in silico approach from statistical models, molecular docking, and ADME/Tox properties

Author(s)

da Silva, Aldineia P. ^[1] ; Chiari, Laise P. A. ^[1] ; Guimaraes, Amanda R. ^[1] ; Honorio, Kathia M. ^[2] ; da Silva, Alberico B. F. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Quim Sao Carlos, Dept Quim & Fis Mol, CP 780, BR-13560970 Sao Carlos, SP - Brazil

^[2] Univ Sao Paulo, Escola Artes Ciencias & Humanidades, BR-03828000 Sao Paulo - Brazil

• Document type: Journal article
• Source: STRUCTURAL CHEMISTRY; v. 32, n. 5, p. 2019-2033, OCT 2021.
• Web of Science Citations: 0

Abstract

Schizophrenia is a psychiatric disorder that affects 20 million people worldwide and the mortality rate is two or three times higher than the average overall population mainly due to high frequency of suicide and other associated comorbidities. The therapeutic approaches used for its treatment, besides do not combat this illness, trigger several side effects, being imperative the development of new medical countermeasures. In the search for new agents, we constructed a statistical model (model A) with a series of aripiprazole-derived using the partial least squares technique, and posteriorly we applied several validation tests to guarantee consistency of model A and its forecasting ability. In addition, molecular docking simulations were employed to extract important information on structural elements involved in the molecular recognition process from receptor-ligand complex. We designed new compounds whose biological activity values were predicted by our model. Among new designed molecules, we highlight compounds 2, 5, 9, and 11 with predicted pK(i) values over 8.5. We underline that the presence of ester moieties attached to the aromatic ring from region A is well tolerated in this position and contributes to increase the pK(i) values; otherwise it is essential that there are no bulky groups in region C. Finally, ADME/Tox properties evaluated via in silico approach for the proposed compounds shed light on their drug-likeness characteristics, indicating that they could be a reliable starting point as potent candidates to further experimental exploration (chemical synthesis, in vitro and in vivo analyses). (AU)

• FAPESP's process: 16/24524-7 - STRUCTURAL ANALYSIS AND MOLECULAR MODELING STUDIES FOR NATURAL AND SYNTHETIC LIGANTS RELATED TO NEGLECTED DISEASES
• Grantee: Kathia Maria Honorio
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07375-0 - CeMEAI - Center for Mathematical Sciences Applied to Industry
• Grantee: Francisco Louzada Neto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC