In silico study to identify new monoamine oxidase type a (MAO-A) selective inhibitors from natural source by virtual screening and molecular dynamics simulation

Abstract

Neurological (such as stroke, Alzheimer's, Parkinson's, epilepsy) and neuropsychiatric (such as autism, migraine, depression, anxiety, stress) disorders continue to be on rising every year with an increase of 20.5% and 13%, respectively. These diseases are critical, life-threatening and in most cases may lead to other precarious human disorders and causing a psychological as well as economic burden on patients and society all over the world that consequently led to a high mortality rate. Notably, Monoamine oxidase (MAO) enzymes are classified as potential drug target for the treatment of such neurological disorders because of their significant role in neurotransmitter degradation that results in the production of certain neurotoxic compounds (such as H2O2, NH3). So far, many MAO inhibitors have been introduced however, the need for a novel potent therapeutic alternative still exists due to significant hypertensive crises, hepatotoxicity and extremely poor selectivity related to nonselective irreversible MAOIs. Therefore, the goal of the current study was to find novel natural compounds that may be used as medicine to treat neurological disorders without causing any harmful side effect. For this purpose, a computational-based virtual screening of 29,000 natural product library (of Natural Product Atlas) from the microbial source is performed through molecular docking and dynamics simulation approach. As a result, about 20 novel potent compounds were successfully shortlisted by implementing molecular docking studies, certain pharmacological, physiological and ADMET properties criteria. Among them, six compounds i.e., NPA000487, 001,637, 007,129, 012,149, 15,149 and NPA0018844 were predicted with a potential to cross BBB and target MAO-A. Furthermore, MD simulations were performed to evaluate the stability and dynamics behavior of these compounds with MAO-A complex for about 50 ns. Eventually, NPA007129, NPA0012149, and NPA0015149 were identified as highly steady complex after 15 ns. Our findings implied that NPA007129, NPA0012149, and NPA0015149 are potential MAO-A inhibitors. Nevertheless, further experimental validation is needed as part of the follow-up investigation.