Browsing by Author "Lawal, Monsurat Motunrayo."

Now showing 1 - 3 of 3

A Computational perspective on the concerted cleavage mechanism of the natural targets of HIV-1 protease.
(2018) Lawal, Monsurat Motunrayo.; Kruger, Hendrik Gerhardus.; Maguire, Glenn Eamonn Mitchel.; Honarparvar, Bahareh.
One infectious disease that has had both a profound health and cultural impact on the human race in recent decades is the Acquired Immune Deficiency Syndrome (AIDS) caused by the Human Immunodeficiency Virus (HIV). A major breakthrough in the treatment of HIV-1 was the use of drugs inhibiting specific enzymes necessary for the replication of the virus. Among these enzymes is HIV-1 protease (PR), which is an important degrading enzyme necessary for the proteolytic cleavage of the Gag and Gag-Pol polyproteins, required for the development of mature virion proteins. The mechanism of action of the HIV-1 PR on the proteolysis of these polyproteins has been a subject of research over the past three decades. Most investigations on this subject have been dedicated to exploring the reaction mechanism of HIV-1 PR on its targets as a stepwise general acid-base process with little attention on a concerted model. One of the shortcomings of the stepwise reaction pathway is the existence of more than two TS moieties, which have led to varying opinions on the exact rate-determining step of the reaction and the protonation pattern of the catalytic aspartate group at the HIV-1 PR active site. Also, there is no consensus on the actual recognition mechanism of the natural substrates by the HIV-1 PR. By means of concerted transition state (TS) structural models, the recognition mode and the reaction mechanism of HIV-1 PR with its natural targets were investigated in this present study. The investigation was designed to elucidate the cleavage of natural substrates by HIV-1 PR using the concerted TS model through the application of computational methods to unravel the recognition and reaction process, compute activation parameters and elucidate quantum chemical properties of the system. Quantum mechanics (QM) methods including the density functional theory (DFT) models and Hartree-Fock (HF), molecular mechanics (MM) and hybrid QM/MM were employed to provide better insight in this topic. Based on experience with concerted TS modelling, the six-membered ring TS structure was proposed. Using a small model system and QM methods (DFT and HF), the enzymatic mechanism of HIV-1 PR was studied as a general acid-base model having both catalytic aspartate group participating and water molecule attacking the natural substrate synchronously. The natural substrate scissile bond strength was also investigated via changes of electronic effects. The proposed concerted six-membered ring TS mechanism of the natural substrate within the entire enzyme was studied using hybrid QM/MM; “Our own N-layered Integrated molecular Orbital and molecular Mechanics” (ONIOM) method. This investigation led us to a new perspective in which an acyclic concerted pathway provided a better approach to the subject than the proposed six-membered model. The natural substrate recognition pattern was therefore investigated using the concerted acyclic TS modelling to examine if HIV-1 (South Africa subtype C, C-SA and subtype B) PRs recognize their substrates in the same manner using ONIOM approach. A major outcome in the present investigation is the computational modelling of a new, potentially active, substrate-based inhibitor through the six-membered concerted cyclic TS modelling and a small system. By modelling the entire enzyme—substrate system using a hybrid QM/MM (ONIOM) method, three different pathways were obtained. (1) A concerted acyclic TS structure, (2) a concerted six-membered cyclic TS model and (3) another sixmembered ring TS model involving two water molecules. The activation free energies obtained for the first and the last pathways were in agreement with in vitro HIV-1 PR hydrolysis data. The mechanism that provides marginally the lowest activation barrier involves an acyclic TS model with one water molecule at the HIV-1 PR active site. The outcome of the study provides a plausible theoretical benchmark for the concerted enzymatic mechanism of HIV-1 PRs which could be applied to related homodimeric protease and perhaps other enzymatic processes. Applying the one-step concerted acyclic catalytic mechanism for two HIV-1 PR subtypes, the recognition phenomena of both enzyme and substrate were studied. It was observed that the studied HIV-1 PR subtypes (B and C-SA) recognize and cleave at both scissile and non-scissile regions of the natural substrate sequences and maintaining preferential specificity for the scissile bonds with characteristic lower activation free energies. Future studies on the reaction mechanism of HIV-1 PR and natural substrates should involve the application of advanced computational techniques to provide plausible answers to some unresolved perspectives. Theoretical investigations on the enzymatic mechanism of HIV-1 PR— natural substrate in years to come, would likely involve the application of sophisticated computational techniques aimed at exploring more than the energetics of the system. The possibility of integrated computational algorithms which do not involve partitioning/restraining/constraining/cropped model systems of the enzyme—substrate mechanism would likely surface in future to accurately elucidate the HIV-1 PR catalytic process on natural substrates/ligands.
Multidimensional computational modeling of Potent BACE1 (β-Secretase) inhibitors towards Alzheimer’s disease treatment.
(2021) Ugbaja, Samuel Chima.; Kumalo, Hezekiel M.; Lawal, Monsurat Motunrayo.
Alzheimer’s disease (AD), as a progressive multifactorial neurodegenerative abnormality of the brain, is often connected with loss or death of neurons as its primary pathogenesis. Another kind of dementia is associated with memory loss and unstable and irrational behaviors, especially among the elderly above 60 years. In South Africa, there are over four million people above the age of 60 years, with an approximation of one hundred and eighty-seven thousand living with dementia. The two distinguishing features (hallmarks) of AD are neurofibrillary tangles and β-amyloid plaques. The β-amyloid plaques result when amyloid precursor protein (APP) is cleaved by β-amyloid precursor protein cleaving enzyme1 (BACE1), otherwise known as β-secretase. Since 1999 the first BACE1 was discovered, it has become a major interest in attempting to develop drugs for the inhibition or reduction of the β-amyloid aggregates in the brain. Reducing or inhibiting the accumulation of β-amyloid has long been the target in the design of drugs for AD treatment. Having a good knowledge of the characteristic properties (BACE1) would assist in the design of potent selective BACE1 inhibitors with fewer or no side effects. Hitherto, only five drugs have been approved by the Food and Drug Administration (FDA) for the remediation of Alzheimer’s disease, and none of the approved drugs targets BACE1. In about twenty years of its discovery, several past and ongoing studies have focused on BACE1 therapeutic roles as a target in managing AD. Several attempts have previously beenmade in designing some small drugmolecules capable of good BACE1 inhibition. Some of the initially discovered BACE1 inhibitors include verubecestat, lanabecestat, atabecestat, and umibecestat (CNP-520). Although these inhibitors significantly lowered β-amyloid plaques in persons having neurological Alzheimer’s at its clinical trials (phase 3), they were suddenly terminated for some health concerns. The termination contributed to the reasons why there are insufficient BACE-targeted drugs for AD treatment. Lately, a novel potent, orally effective, and highly selective AM-6494 BACE1 inhibitor was discovered. This novel BACE1 inhibitor exhibited no fur coloration and common skin alteration, as observed with some initial BACE1 inhibitors. AM-6494 with an IC50 value of 0.4 nM in vivo is presently selected and at the preclinical phase trials. Before this study, the inhibition properties of this novel BACE1 inhibitor at the atomistic and molecular level of BACE1 inhibition remained very unclear. The first manuscript (chapter two) is a literature review on Alzheimer's disease and β-secretase inhibition: An update focusing on computer-aided inhibitor design. We provide an introductory background of the subject with a brief discussion on Alzheimer’s pathology. The review features computational methods involved in designing BACE1 inhibitors including the discontinued drugs. Using the topical keywords BACE1, inhibitor design, and computational/theoretical study in theWeb of Science and Scopus database, we retrieved over 49 relevant articles. The search years are from 2010 and 2020, with analysis conducted from May 2020 to March 2021. Our second manuscript (chapter three) reviewed BACE1 exosite-binding antibody and allosteric inhibition as an alternative therapeutic development. We studied BACE1 biological functions, the pathogenesis of the associated diseases, and the enzymatic properties of the APP site cleavage. We suggested an extensive application of advanced computational simulations in the investigation of anti-BACE1 body and allosteric exosites. It is believed that this investigation will further help in reducing the associated challenges with designing BACE1 inhibitors while exploring the opportunities in the design of allosteric antibodies. The review also revealed that some molecules exhibited dual binding sites at the active site and allosteric site. As a result, we recommend an extensive investigation of the binding free energy beyond molecular docking (such as advanced molecular dynamic simulations) as this promises to reveal the actual binding site for the compounds under investigation. Chapter four contains the detailed computational science techniques which cover the application of the vitally essential methods of molecular mechanics (MM), quantum mechanics (QM), hybrid of QM/MM, basis sets, and other computational instruments employed in this study. In the third manuscript (chapter five), we carried out computational simulations of AM-6494 and CNP- 520.CNP520 was one of the earliest BACE1 drugs that were terminated, chosen in this study forcomparative reasons. This simulation was to elucidate and understand the binding affinities of these two inhibitors at the atomistic level. We explored the quantum mechanics (QM) density functional theory (DFT) and hybrid QM/MM of Our Own N-layered Integrated molecular Orbital and Molecular Mechanics (ONIOM) in these simulations. These computational approaches helped in predicting the electronic properties of AM-6494 and CNP-520, including their binding energies when in complex with BACE1. Considering the debates on which protonated forms of Asp 32 and Asp 288 gives a more favorable binding energy, we analysed the two forms which involved the protonation and un-protonation of Asp 32 and Asp 228.The ONIOM protonated model calculation gave binding free energy of -33.463 kcal/mol (CNP-520)and 62.849 kcal/mol (AM-6494) while the binding free energy of -59.758 kcal/mol was observed for the unprotonated AM-6494 model. These results show the protonated model as a more favourable binding free energy when compared with the un-protonation AM-6494 model. Further thermochemistry processes coupled with molecular interaction plots indicate that AM-6494 has better inhibition properties thanCNP-520.However, it was observed that the protonation and the un-protonation of Asp 32 and Asp 228 modelscould adequately illustrate the interatomic binding of the ligands-BACE1 complex. To further explicate the binding mechanism, conformational and structural dynamism of AM-6494 relative to CNP-520 in complex with BACE1, we carried out advanced computational simulations in the fourth manuscript (chapter six). The extensive application of accelerated molecular dynamics simulations, as well as principal component analysis, were involved. From the results, AM-6494 further exhibited higher binding affinity with van der Waals as the predominant contributing energy relative to CNP-520. Furthermore, conformational analysis of the β-hairpin (flap) within the BACE1 active site exhibited efficient closed flap conformations in complex withAM-6494 relative to CNP-520, whichmostly alternated between closed and semi-open conformational dynamics. These observations further elucidate that AM- 6494 shows higher inhibitory potential towards BACE1. The catalytic dyad (Asp32/228), Tyr14, Leu30, Tyr71, and Gly230 constitute essential residues in both AM-6494 potencies CNP-520 at the BACE1 binding interface. The results from these extensive computational simulations and analysis undoubtedly elucidate AM-6494 higher inhibition potentials that will further help develop new molecules with improved potency and selectivity for BACE1. Besides, grasping the comprehensive molecular mechanisms of the selected inhibitors would also help in fundamental pharmacophore investigation when designing BACE1 inhibitors. Finally, the implementation of computational techniques in the designing of BACE1 inhibitors has been quite interesting. Nevertheless, the designing of potent BACE1 inhibitors through the computational application of the QM method such as the density functional theory (DFT), MM, and a hybrid QM/MM method should be extensively explored. We highly recommend that experimentalists should always collaborate with computational chemists to save time and other resources. ISIZULU ABSTRACT Iqoqa Isifo se-Alzheimer (AD), njengoba siqhubeka siyinhlanganisela yezimbangela ze- neurodegenerative engajwayelekile ebuchosheni, isikhathi esiningi kuxhumana nokulahleka noma ukufa kwama-neurons njengongqaphambili we-pathogenesis. Kungolunye uhlobo lwedementia oluhambisana nokulahlekelwa ukukhumbula kanyenokuxenga kanye nokuphanjanelwa ingqondo, ikakhulukazi kubantu abadala esebeneminyaka engaphezulu kuka-60. ENingizimu Afrikha, kunabantu abangaphezulu kwezigidi ezine abangephezulu kweminyaka ewu-60, ngokuhlawumbisela nje abayinkulungwane namashumi ayisishayangolombili nesikhombisa baphila nedemetia. Zimbili izimpawu ezihlukanisekayo ze-AD ziba-ama-neurofibrillary tangles kanye ne-B-amyloid plaques. I-B-amyloid plaques ingumphumela ngesikhathi i-amyloid eyiprotheni egijimayo iqhwakele oketshezini i-enzyme1 (BACEI), ngale kwalokho yaziwanjenge B-secretase. Kusukela ngo 1999 i-BAC1 yatholakala, isiphenduke ungqaphambili emizamweni yokwakha isidakamizwa sokwehlisa i-B-amyloid ngokwezinga lengqondo. Ngokunciphisa ukwanda kwe-B-amyloid isiphenduke okuqondiwe mayelana nokuqopha isidakamizwa ukuze kwelashwe i-AD. Ukuba nolwazi oluhle oluthinta isici sezakhi ze-BACE1 kuzosiza ekubazeni amandla akhethiwe i-BACE1 ukuvimbela imiphumela engaqondiwe. Kuze kube manje mihlanu imithi esiphasisiwe ngabezokuphatha ukudla kanye nezidakamizwa (FDA) ukwelapha isifo se-Alzheimer kanye nokuthi azikho kulezi eziphasisiwe izidakamizwa ebhekana ngqo ne-BACE1. Emva kokuba selitholakele lapho nje eminyakeni engu 20, sekunezinye esikhathini esedlule kanye nezifundo ezisaqhubeka zigxile ngokubheka kakhulu iqhaza lokwelapha i-BAC1 njengokuqondiswe ekungameleni u-AD. Imizamo eminingana yenziwa esikhathini esedlule ukuqopha uketshezi lwezidakamizwa olukwazi ukuvimba kahle i-BACE1. i-B-amyloid plaques kumuntu one-neurological ye-Alzheimer’s kumzamo (isigaba 3), kwabuye kwanqanyulwa ngenxa yokukhathazeka ngokwezempilo. Ukunqanyulwa kwanikela kuzizathu zokusilele kwezidakamizwa okuqondene nokulashwa kwe-AD. Kamuva, i-novel enamandla, ngisho ngawo umlomo kanye neyakhethwa ngezinga eliphezulu i-AM-6494 BACE1 evikelayo yatholakala. Le noveli i-BACE1 evimbayo yabukisa hhayi ukushintsha kombala woboya kanye nokushintsha kwesikhumba okujwayelekile, njengoba kubukwa nezivimbo zokuqala ze-BACE1. I-AM-6494 ne-IC50 enobumqoka buka 0.4nM kuyo i-vivo ekhethwa ngokwamanje kanye nesigaba sembulambethe yemizamo. Ngaphambi kwalesi sifundo, izakhi zesivimbela zale noveli i-BACE1zivimba ngokwe-atomistic kanye neqophelo le-molecular ye-B ACE1evimbayo kusale nje kungacacile. Umqulu wokuqala (isahluko sesibili) ukubuyekezwa kwesifo se-Alzheimer’s kanye no-B-secretase ovimbayo: ezikhumbuzayo ezigxile ngokusizwa yikhompuyutha eyisivimbo ngokwakhiwa. Sethula isendlalelo sesifundo kanye nengxoxo kafushane nezimbangela nemiphumela ye-Alzheimer. Ukubukezwa kwezimpawu zendlela zobukhompuyutha kufaka ekuqopheni isivimbo se-BACE1 nokuqhutshekiswa kwesidakamizwa. Ngokusebenzisa ofeleba begama BACE1, kusho ukwakha isivimbo, kanye nesifundo senjulalwazi kulwembu lobuchwepheshe kanye ne-Scopus sesizindalwazi. Sathola amaphepha acwaningiwe anokuhlobana angaphezulu kuka 49. Unyaka wokuthungatha usukela ku2010 kuya ku2020, nohlaziyo lwenziwa kusukela kuNhlaba 2020 kuya kuNdasa 2021. Umqulu wethu wesibili (isahluko sesithathu) sabuyekeza i-BACE ehlanganisa i-exosite antibody kanye ne-allosteric yokuthuthukisa ukwelashwa. Sakufunda ukusebenza kwesayensi yokuphila ye-BACE1, i-pathogenesis ehambisana nezifo kanye nezakhi zama-enzymatic esizinda sokuhlukana se-APP. Saphakamisa ukufakwa okunzulu nokucokeme kokulinganisa ngobuchwepheshe bekhompuyutha ekuphenyeni ama-anti-BACE1 omzimba kanye ne-allosteric ye-exosites. Kuyakholeka ukuthi uphenyo luzoqhubeka nokusiza ekwehliseni izinselelo ezihambisana nokwakha isithiyo se-BACE1 ngesikhathi kuhlolwa amathuba okwakheka kwe-allosteric yama-antibodies. Ubuyekezo luphinde lwaveza uketshezi olubukisa isizinda sokuhlanganisa kabili kusizinda esikhuthele kanye nesizinda se-allosteric. Umphumela, kube ukwenza isincomo mayelana nocwaningo olunzulu oluzohlanganisa umfutho okhululekile odlulele ku-molecular docking (njengesicokeme se-molecular yokuhlukahlukana kokulinganisa) njengoba lokhu kuthembisa ukuveza isiza esibopha ngempela ama-compounds angaphansi Isahluko sesine siqukethe imininingwane ngamaqhinga e-computational sayensi efaka isicelo esibalulekile sezindlela ezibalulekile ze-molecular mechanics (MM), i-quantum mechanics (QM), i-hybrid ye-QM/MM, ngesisekelo samasethi kanye namanye amathuluzi ekhompuyutha akhethwa kulesi sifundo. Kumqulu wesithathu (isahluko sesihlanu), siqhube isilinganiso se-computational ye-AM-6494 kanye CNP-520.I-CNP-520 kwakungenye yezidakamizwa zokuqala zeBACE1 ezashatshalaliswa, zakhethwa kulesisifundo ngezizathu zokuqhathanisa. Ukulinganisa kwakuchaza kanye nokuqonda ukusondelana ngokuhlanganiswa kwezithiyo ezimbili kusigaba se-atomistic. Kwahlolwa i-quatum mechanics (QM) yesisindo yokusebenza kwenjulalwazi (DFT) kanye ne-hybrid QM/MM yokwethu okuno-N oluwugqinsi lwe-molecular Orbital kanye ne-Molecular Mechanics (ONIOM) kulolu linganiso. Lezi zindlelakwenza ze-computational zasiza ekuqageleni kwezakhiwo zama-electronic e-AM-6494 kanye CNP-520, kungena namandla okuhlanganisa ngesikhathi kuba lukhuni ne-BACE1. Ngokucabanga izinkulumo mpikiswano mayelana nokuma kwe-protonated ye-Asp32 kanye Asp288 kunika ukuvumelana namandla okuhlanganisa, nokuhlaziya izimo ezimbili ezifaka i-protonation kanye ne-unprotonation ye-Asp32 kanye Asp228. I-ONIOM ye-protonated yomfanekiso wokubala wanikeza amandla akhululekile okuhlanganisa -33,463kcal/mol (NP-520) kanye 62.849 kcal /mol kwavela i-unprotonate ye-AM6494. Imiphumela itshengisa ukuthi i-protonated iyisifanekiso njengoba kuyisona esivumela ukuhlanganiswa ngokukhululeka ngesikhathi lapho bekuqhathanisa ne-unprotonation yomfanekiso u-AM-649. Kuqhutshelwa phambili nemisebenzi ye-thermochemistry kuhlangana nokudlelana ne-molecular plots kutshengisa ukuthi i-AM-649 inezakhiwo ezinhle zokuvimba kune CNP-520. Yize kunjalo kwabonakala ukuthi i-protonation kanye ne-unprotonation ye-Asp32 kanye neyomfanekiso owu- Asp228 bekungatshengisa ngokwenele ukuhlanganisa ngokwe-interatomic yama-ligands EBACE1 ebilukhuni. be-BACE1 ngokwedlulele isilinganiso se-computational. Ukwenza ngokujulile kuphangiswa isilinganiso se-molecular ngokuhlukana, kwakakwa nohlaziyo olusemqoka lwezingxenyana. Imiphumela ye-AM-6494 yaqhubeka yatshengisa ukusondelana kokuhlanganiswayo no-van der Waals njengohamba phambili ekunikeleni amandla ahlobene ne-CNP-520. Ukuvuma kohlaziyo lwe-B-hairpin ngaphakathi ku-BACE1 kutshengiswa esizeni esiphilayo esivala ngendlela umnyakazo wokuvuma kobunkimbinkimbi be-AM-6494 ehlobene neCNP-520, ngokuvamile eshitshashintshayo phakathi kwevalekile kanye nezishaya sakuvuleka kokuvuma okunhlobonhlobo. Lokhu kuhlolwa kuqhubeke kwachazwa ngokuthi i-AM-6494 itshengisa ukuvimba okukhulu nokunethemba mayelana ne-BACE1. Isikhuthazizinguquko se-dyad (Asp32/228), Tyr14, Leu 30, Tyr 71, kanye ne-Gly230 kwakha izinsalela ezibalulekile nxazombili kuAM-6494ne-potencies yeCNP-520 kuBACE1 nesixhumanisi esihlanganisayo. Imiphumela ivela kulama-computational anzulu ayisilinganiso kanye nohlaziyo olucacisa ngokungangabazi i-AM-6494 enesivimbelo esiphakeme esingakwazi ukuqhubeka nokusiza intuthuko yama-molecules amasha anamandla athuthukile kanye nakhethelwe i-BACE1. Ngaphandle kwalokhu, ukucosha izinkambiso ezibanzi ze-moleculor mayelana nezivimbo ezikhethiwe kuzosiza mayelana nophenyo olubalulekile lwe- pharmacophore ngesikhathi kuqoshwa izivimbo se-BACE1. Ekugcineni, ukwenziwa kwe-computational ngokwamacebo ekubazeni izivimbo ze-BACE1 kube into ehlaba umxhwele. Nokho ukubaza izivimbo ezinamandla ze-BACE1 ngokusebenzisa i-computational yendlela ye-QM njengenjulalwazi yesisindo esisebenzayo (DFT), MM, kanye nendlela ye-hybrid QM/MM kufanele iphenywe kanzulu. Sincoma kakhulu ukuthi ongoti abenza izibonisi kufanele njalo bahlangane nama-computational chemists ukonga isikhathi kanye nezinye izinsiza.
Theoretical study on the esterification of methanol with acetic acid and acid halides.
(2015) Lawal, Monsurat Motunrayo.; Honarparvar, Bahareh.; Maguire, Glenn Eamonn Mitchel.; Kruger, Hendrik Gerhardus.
Esters are a unique class of organic compounds whose production and reactivity are examined in chemical industries and research laboratories throughout the world on a daily basis. An ongoing advancement in esterification reactions is applied in biofuel production from natural and waste organic sources. The roles of esters in daily and industrial activity are enormous, which includes: perfumery, glues, solvents in chemical reactions, dye production, cosmetics removal and functional groups in the production of pharmaceutical drugs. Dating back to the 1890s, Fischer esterification remained a crucial process through which esters are formed by coupling carboxylic acid with alcohol in the presence of an acid. For the past three decades, focus on esterification in the presence of solid acids as well as eco-friendly catalysts have been developed to enhance this process between carboxylic acids and alcohols. Important derivatives of esters are acid anhydrides and acid halides. They produce esters when reacted with alcohol either in presence or absence of catalyst. A number of mechanisms involved in ester formation have been proposed and kinetics obtained via experiments while little attention has been paid to exploiting mechanistic aspects at the molecular level. Herein, a thorough investigation on ester formation from acetic acid and acid halides (acetyl fluoride, chloride, bromide and iodide) reacting with methanol is done using density functional methods. In the first step, efforts were made to examine the feasibility of an uncatalyzed model for this reaction in gas and solvent (methanol only). Before this could be achieved, a comprehensive investigation was done to assign a suitable basis set in which defTZVP was upheld for being sufficient and efficient for all atoms involved in this project at the B3LYP and M06-2X levels of theory. A notable conclusion from the basis sets investigation is that a broad basis set is required to span all halogen atoms. Esterification of these substrates to yield methyl acetate was modelled to have occurred in a concerted manner through three different cyclic transition states. The one-step 6-membered mechanism gives lower activation energies for XAc with X = Cl, Br and I. On the other hand, the two-step 6-membered concerted model gave the lowest activation barriers for XAc with X = OH and F. The calculated thermodynamic parameters gave free energy barriers of 35.4 and 21.9 kcal mol-1 for acetic acid and acetyl chloride reaction with methanol respectively. This observation is in excellent agreement with experimental values of about 34 and 20 kcal mol-1 from literature. The esterification reaction of acetic acid and its halide analogues with methanol was also studied in the presence of an acid catalyst using the M06-2X hybrid density functional and the defTZVP basis set. The reaction was modelled as a one-step concerted 6-membered cyclic transition state. An activation of 19.77 kcal mol-1 which is in reasonable agreement with experimental value was obtained. The simple one step concerted 6-membered ring mechanism provides a suitable description of the acid-catalyzed esterification reaction. Esterification of acid halides (X = Cl, Br and I) with methanol in the presence of a hydrogen ion also produced values confirming their spontaneous reactivity while acetyl fluoride vary with a high solution phase free energy of 9 kcal mol-1. The outcome of this research has provided a rational molecular level understanding on the concerted mechanism of esterification via 6-membered ring transition states.