Molecular modeling methods and Computer-Aided Molecular Design Formalism for elucidating the mechanism of action of matrix metalloproteinases inhibitors.

• Grant number: 10/19142-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2011
• End date: February 28, 2015
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Silvia Berlanga de Moraes Barros
• Grantee: Kely Medeiros Turra
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cutaneous melanoma, one of the most aggressive form of skin cancer, is considered a major global public health problem and its incidence has grown rapidly in recent years, including Brazil. Therapies available for the advanced stage of melanoma, however, are far from satisfactory and effective, given that this cancer is refractory to most chemotherapeutic medicines available and that the drugs used in its treatment have high toxicity and low efficiency, especially when the disease is metastatic.Faced with the lack of effective therapeutic alternatives, the development of new drugs to treat this cancer is necessary. Compounds capable of inhibiting matrix metalloproteinase activity, modulating cellular apoptosis and regulate the intracellular redox system constitute promising therapeutic agents.According to studies by Ropke et al. (2006) and Brohem et. al. (2009), using the compound of natural origin 4-nerolidylcatechol (4-NC) isolated from Pothomorphe sp., showed positive results for the treatment of melanoma. The 4-NC was able to act in several important biochemical steps involved in the progression of this disease, however, its molecular level mechanism of action is not fully elucidated.This research project proposes the application of molecular modeling methods and formalisms of CAMD (Computer-Aided Molecular Design) to generate models of interaction between the 4-NC and the enzymes involved in the development of metastasis in melanoma, map the site interaction of these targets and, therefore, propose the mechanism of action of 4-NC.

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TURRA, KELY MEDEIROS; MESQUITA PASQUALOTO, KERLY FERNANDA; DE MORAES BARROS, SILVIA BERLANGA. A novel set of ss-N-biaryl ether sulfonamide hydroxamates as potential MMPs inhibitors: Molecular dynamics simulations and molecular properties evaluation. International Journal of Quantum Chemistry, v. 112, n. 20, SI, p. 3374-3389, OCT 15 2012. (10/19142-1)

TURRA, KELY MEDEIROS; RIVELLI, DIOGO PINEDA; DE MORAES BARROS, SILVIA BERLANGA; MESQUITA PASQUALOTO, KERLY FERNANDA. Constructing and Validating 3D-pharmacophore Models to a Set of MMP-9 Inhibitors for Designing Novel Anti-melanoma Agents. MOLECULAR INFORMATICS, v. 35, n. 6-7, p. 238-252, JUL 2016. (10/19142-1)

TURRA, KELY MEDEIROS; MESQUITA PASQUALOTO, KERLY FERNANDA; DE MORAES BARROS, SILVIA BERLANGA. A novel set of ss-N-biaryl ether sulfonamide hydroxamates as potential MMPs inhibitors: Molecular dynamics simulations and molecular properties evaluation. International Journal of Quantum Chemistry, v. 112, n. 20, p. 16-pg., 2012-10-15. (10/19142-1)

TURRA, KELY MEDEIROS; RIVELLI, DIOGO PINEDA; DE MORAES BARROS, SILVIA BERLANGA; MESQUITA PASQUALOTO, KERLY FERNANDA. Predicting Novel Antitumor Agents: 3D-Pharmacophore Mapping of beta-N-biaryl Ether Sulfonamide-Based Hydroxamates as Potentially MMP-2 Inhibitors. MOLECULAR INFORMATICS, v. 33, n. 9, p. 573-587, SEP 2014. (10/19142-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

TURRA, Kely Medeiros. Molecular modeling methods and computer-aided molecular design (CAMD) formalisms for elucidating the mechanism of action of matrix metalloproteinases inhibitors. 2015. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.